- Pentuline derivatives and preparation methods and applications thereof
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The present invention provides a chingotine derivative, the structural formula of which is shown in formula I. Specifically, the R is any of the following groups: p-chlorophenylacetyl, 2,4-dichlorophenylacetyl, m-chlorophenylacetyl, 3,4-dichlorophenylacet
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Paragraph 0060-0064
(2022/01/12)
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- Identification of BR102910 as a selective fibroblast activation protein (FAP) inhibitor
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Fibroblast activation protein (FAP) belongs to the family of prolyl-specific serine proteases and displays both exopeptidase and endopeptidase activities. FAP expression is undetectable in most normal adult tissues, but is greatly upregulated in sites of tissue remodeling, which include fibrosis, inflammation and cancer. Due to its restricted expression pattern and dual enzymatic activities, FAP inhibition is investigated as a therapeutic option for several diseases. In the present study, we described the structure–activity relationship of several synthesized compounds against DPPIV and prolyl oligopeptidase (PREP). In particular, BR102910 (compound 24) showed nanomolar potency and high selectivity. Moreover, the in vivo FAP inhibition study of BR102910 (compound 24) using C57BL/6J mice demonstrated exceptional profiles and satisfactory FAP inhibition efficacy. Based on excellent in vitro and in vivo profiles, the potential of BR102910 (compound 24) as a lead candidate for the treatment of type 2 diabetes is considered.
- Jung, Hui Jin,Nam, Eun Hye,Park, Jin Young,Ghosh, Prithwish,Kim, In Su
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supporting information
(2021/02/26)
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- Design, synthesis, biological evaluation and silico prediction of novel sinomenine derivatives
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Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty‐three compounds were synthesized and characterized by spectroscopy (IR,1H‐NMR,13C‐NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF‐7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine‐containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer‐related core targets and verified their interaction with derivatives through molecular docking. The chlorine‐containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine‐containing derivatives might be a promising lead for the development of new anticancer agents.
- Cui, Dongmei,Gao, Mingjie,Li, Jinjie,Li, Shoujie,Nian, Xin,Zhang, Chen,Zhang, Liyu,Zhao, Changqi
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- Enantioselective Synthesis of 2-Functionalized Tetrahydroquinolines through Biomimetic Reduction
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Biomimetic asymmetric reduction of 2-functionalized quinolines has been successfully developed with the chiral and regenerable NAD(P)H model CYNAM in the presence of transfer catalyst simple achiral phosphoric acids, providing the chiral 2-functionalized
- Zhao, Zi-Biao,Wang, Jie,Zhu, Zhou-Hao,Chen, Mu-Wang,Zhou, Yong-Gui
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supporting information
p. 9112 - 9117
(2021/11/24)
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- N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
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A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 μM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10?3 s?1) from the catalytic domain.
- Fang, Hai-Lian,He, Jie-Ling,Li, Wei-Yi,Liu, Shan-Shan,Ni, Wei-Wei,Pan, Xing-Ming,Xiao, Zhu-Ping,Ye, Ya-Xi,Yi, Juan,Zhou, Mi,Zhou, Tian-Li,Zhu, Hai-Liang
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p. 404 - 413
(2020/01/03)
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- Synthesis of novel nicotinic ligands with multimodal action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters
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Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 μM for h-DAT and 0.031 ± 0.006 μM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 μM for α4β2 nAChR and 0.075 ± 0.009 μM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4β2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.
- González-Gutiérrez, Juan Pablo,Pessoa-Mahana, Hernán Armando,Iturriaga-Vásquez, Patricio Ernesto,Reyes-Parada, Miguel Iván,Guerra-Díaz, Nicolas Esteban,Hodar-Salazar, Martin,Viscarra, Franco,Paillali, Pablo,Nú?ez-Vivanco, Gabriel,Lorca-Carvajal, Marcos Antonio,Mella-Raipán, Jaime,Zú?iga, María Carolina
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- Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage
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Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were synthesized and evaluated for their anti-filovirus activiti
- Zhang, Xin,Liu, Qiang,Zhang, Na,Li, Qian–Qian,Liu, Zhan–Dong,Li, Ying–Hong,Gao, Li–Mei,Wang, You–Chun,Deng, Hong–Bin,Song, Dan–Qing
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- Structural insight into the optimization of ethyl 5-hydroxybenzo[g]indol-3-carboxylates and their bioisosteric analogues as 5-LO/m-PGES-1 dual inhibitors able to suppress inflammation
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The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties. In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway.
- Bruno, Ferdinando,Errico, Suann,Pace, Simona,Nawrozkij, Maxim B.,Mkrtchyan, Arthur S.,Guida, Francesca,Maisto, Rosa,Olga?, Abdurrahman,D'Amico, Michele,Maione, Sabatino,De Rosa, Mario,Banoglu, Erden,Werz, Oliver,Fiorentino, Antonio,Filosa, Rosanna
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p. 946 - 960
(2018/07/24)
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- Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues
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In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.
- Verschueren, Klaas,Cobbaut, Mathias,Demaerel, Joachim,Saadah, Lina,Voet, Arnout R. D.,Van Lint, Johan,De Borggraeve, Wim M.
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p. 640 - 646
(2017/03/30)
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- Ruthenium-catalysed one-pot regio- and diastereoselective synthesis of pyrrolo[1,2-a] indoles via cascade C-H functionalization/annulation
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A cascade approach has been developed towards dual C-C bond formation via consecutive C-H functionalization/cyclization giving access to pyrrolo[1,2-a]indoles in a highly regio- and diastereoselective manner using catalytic [Ru(p-cymene)Cl2]2. The methodology was further expanded to attain pentacyclic structures involving manifold C-C bond creation.
- Singh, Sukhdev,Butani, Himanshu H.,Vachhani, Dipak D.,Shah, Anamik,Van Der Eycken, Erik V.
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supporting information
p. 10812 - 10815
(2017/10/10)
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- PROCESS FOR THE PREPARATION OF PERHYDROQUINOXALINE DERIVATIVES
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The present invention relates to a process for the preparation of perhydroquinoxaline compounds according to the general formula (1) comprising the steps of a) reacting 5,6,7,8-tetrahydroquinoxalin-5-ol with a protection agent; b) catalytically hydrogenat
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Page/Page column 30; 31
(2016/06/21)
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- SUBSTITUTED BENZOTHIAZOLES AND THERAPEUTIC USES THEREOF FOR THE TREATMENT OF HUMAN DISEASES
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The invention relates to a family of differently substituted benzothiazoles having an inhibitory activity against the enzyme casein kinase 1 (CK1), as a result of which they are suitable for use in the treatment or prevention of diseases caused by this enzyme, particularly diseases associated with circadian rhythm and inflammatory, autoimmune, psychiatric, neurodegenerative, neurological or ophthalmological diseases, as well as for inducing cell regeneration.
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Paragraph 0087
(2015/12/18)
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- Synthesis and pharmacological evaluation of 5-pyrrolidinylquinoxalines as a novel class of peripherally restricted κ-opioid receptor agonists
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5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted κ-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine κ pharmacophore allows
- Bourgeois, Christian,Werfel, Elena,Galla, Fabian,Lehmkuhl, Kirstin,Torres-Gómez, Héctor,Schepmann, Dirk,K?gel, Babette,Christoph, Thomas,Stra?burger, Wolfgang,Englberger, Werner,Soeberdt, Michael,Hüwel, Sabine,Galla, Hans-Joachim,Wünsch, Bernhard
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supporting information
p. 6845 - 6860
(2014/11/07)
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- Stereoselective synthesis of cis,cis-configured vicinal triamines
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The first stereoselective synthesis of a cis,cis-configured vicinal triamine was achieved, starting from N-cyclohexenylpyrrolidone (10). The reaction sequence consists of the stereoselective construction of the trans-configured 1,3-diamide 14, trans-to-ci
- Schulte, Adrian,Saito, Susumu,Wünsch, Bernhard
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supporting information
p. 5749 - 5756
(2014/10/15)
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- Specific features of HIV-1 integrase inhibition by bisphosphonate derivatives
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The integration of viral DNA into the cell genome is one of the key steps in the replication cycle of human immunodeficiency virus type 1 (HIV-1). Therefore, the viral enzyme integrase (IN) catalyzing this process is of great interest as a target for new
- Agapkina, Julia,Yanvarev, Dmitry,Anisenko, Andrey,Korolev, Sergey,Veps?l?inen, Jouko,Kochetkov, Sergey,Gottikh, Marina
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- Identification of ML251, a potent inhibitor of T. brucei and T. cruzi phosphofructokinase
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Human African Trypanosomiasis (HAT) is a severe, often fatal disease caused by the parasitic protist Trypanosoma brucei. The glycolytic pathway has been identified as the sole mechanism for ATP generation in the infective stage of these organisms, and several glycolytic enzymes, phosphofructokinase (PFK) in particular, have shown promise as potential drug targets. Herein, we describe the discovery of ML251, a novel nanomolar inhibitor of T. brucei PFK, and the structure-activity relationships within the series.
- Brimacombe, Kyle R.,Walsh, Martin J.,Liu, Li,Vasquez-Valdivieso, Montserrat G.,Morgan, Hugh P.,McNae, Iain,Fothergill-Gilmore, Linda A.,Michels, Paul A. M.,Auld, Douglas S.,Simeonov, Anton,Walkinshaw, Malcolm D.,Shen, Min,Boxer, Matthew B.
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supporting information
p. 12 - 17
(2014/02/14)
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- Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1δ inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood-brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.
- Salado, Irene G.,Redondo, Miriam,Bello, Murilo L.,Perez, Concepción,Liachko, Nicole F.,Kraemer, Brian C.,Miguel, Laetitia,Lecourtois, Magalie,Gil, Carmen,Martinez, Ana,Perez, Daniel I.
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p. 2755 - 2772
(2014/04/17)
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- PERHYDROQUINOXALINE DERIVATIVES USEFUL AS ANALGESICS
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The present invention relates to perhydroquinoxaline compounds according to the general formula (1), their use as a medicament, in particular as analgesic, antipruritic and antiinflammatory agents, and their preparation.
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Page/Page column 84
(2014/12/12)
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- Palladium-catalyzed aryl C-H olefination with unactivated, aliphatic alkenes
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Palladium-catalyzed coupling between aryl halides and alkenes (Mizoroki-Heck reaction) is one of the most popular reactions for synthesizing complex organic molecules. The limited availability, problematic synthesis, and higher cost of aryl halide precursors (or their equivalents) have encouraged exploration of direct olefination of aryl carbon-hydrogen (C-H) bonds (Fujiwara-Moritani reaction). Despite significant progress, the restricted substrate scope, in particular noncompliance of unactivated aliphatic olefins, has discouraged the use of this greener alternative. Overcoming this serious limitation, we report here a palladium-catalyzed chelation-assisted ortho C-H bond olefination of phenylacetic acid derivatives with unactivated, aliphatic alkenes in good to excellent yields with high regio- and stereoselectivities. The versatility of this operationally simple method has been demonstrated through drug diversification and sequential C-H olefination for synthesizing divinylbenzene derivatives.
- Deb, Arghya,Bag, Sukdev,Kancherla, Rajesh,Maiti, Debabrata
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supporting information
p. 13602 - 13605
(2015/02/05)
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- PERHYDROQUINOXALINE DERIVATIVES USEFUL AS ANALGESICS
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The present invention relates to perhydroquinoxaline compounds according to the general formula (1), their use as a medicament, in particular as analgesic, antipruritic antiinflammatory agents, and their preparation.
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Page/Page column 45
(2014/12/12)
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- Asymmetric hydrogenation of α- Or β-acyloxy α,β- unsaturated phosphonates catalyzed by a Rh(i) complex of monodentate phosphoramidite
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The Rh(i) complex of a monodentate phosphoramidite bearing a primary amine moiety (DpenPhos) has been disclosed to be highly efficient for the asymmetric hydrogenation of a variety of α- or β-acyloxy α,β- unsaturated phosphonates, providing the corresponding biologically important chiral α- or β-hydroxy phosphonic acid derivatives with excellent enantioselectivities (90->99% ee).
- Zhang, Jinzhu,Dong, Kaiwu,Wang, Zheng,Ding, Kuiling
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supporting information; scheme or table
p. 1598 - 1601
(2012/03/22)
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- SUBSTITUTED SULFONAMIDES USEFUL AS ANTIAPOPTOTIC BCL INHIBITORS
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Disclosed are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: W and Q and G are defined herein. Also disclosed are methods of using such compounds as inhibitors of Bcl-2 family antiapoptotic proteins for the treatment of cancer; and pharmaceutical compositions comprising such compounds.
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Page/Page column 149-150
(2012/12/13)
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- Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488
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Screening of the Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC50 value of 59nM as determined in our T.brucei invitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure-activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound.
- Smith, Victoria C.,Cleghorn, Laura A. T.,Woodland, Andrew,Spinks, Daniel,Hallyburton, Irene,Collie, Iain T.,YiMok,Norval, Suzanne,Brenk, Ruth,Fairlamb, Alan H.,Frearson, Julie A.,Read, Kevin D.,Gilbert, Ian H.,Wyatt, Paul G.
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experimental part
p. 1832 - 1840
(2012/06/18)
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- Conformationally constrained κ receptor agonists: Stereoselective synthesis and pharmacological evaluation of 6,8-diazabicyclo[3.2.2]nonane Derivatives
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Three sets of stereoisomeric bicyclic κ agonists with defined orientation of the pharmacophoric elements pyrrolidine and dichlorophenylacetamide were stereoselectively prepared and pharmacologically evaluated. Stereoselective reduction, reductive amination, and Mitsunobu inversions were the key steps for the establishment of the desired stereochemistry. The κ affinity decreased in the following order depending on the N-substituent: CO2CH3 > benzyl > COCH 2CH3. Bicyclic derivatives with (1S,2R,5R)-configuration showed the highest κ receptor affinity, which led to dihedral angles of 97° and 45° for the N(pyrrolidine)-C-C-N(phenylacetamide) structural element. The most potent κ agonist of this series was (+)-methyl (1S,2R,5R)-8-[2-(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-yl)-6, 8-diazabicyclo[3.2.2]nonane-6-carboxylate (ent-23, WMS-0121) with an K i value of 1.0 nM. ent-23 revealed high selectivity against the other classical opioid receptors and related receptor systems. In the [ 35S]GTPγS-binding assay at human κ-opioid receptors, ent-23 was proved to be a full agonist with the same EC50 value (87 nM) as the prototypical full agonist U-69,593 (EC50 = 80 nM).
- Geiger, Christian,Zelenka, Christel,Lehmkuhl, Kirstin,Schepmann, Dirk,Englberger, Werner,Wünsch, Bernhard
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supporting information; experimental part
p. 4212 - 4222
(2010/08/22)
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- BICYCLIC PYRIMIDINONES AND USES THEREOF
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The present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. A pharmaceutical composition or medicament comprising a compoundof Formula I is also provided.
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Page/Page column 71
(2008/12/06)
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- INHIBITORS OF VOLTAGE-GATED SODIUM CHANNELS
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Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-gated sodium channels. More particularly, the invention provides heterocyclic aryl sulfonamides, compo
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Page/Page column 37-38
(2008/06/13)
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- PHENOXYACETIC ACID DERIVATIVES USEFUL FOR TREATING RESPIRATORY DISEASES
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The invention relates to substituted phenoxyacetic acids as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.Formula (I)
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Page/Page column 108
(2008/06/13)
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- Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids
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(+)-1(R)-Coclaurine (1) and (-)-1(S)-norcoclaurine (3), together with quercetin 3-O-β-d-glucuronide (4), were isolated from the leaves of Nelumbo nucifera (Nymphaceae), and identified as anti-HIV principles. These compounds can serve as new leads for furt
- Kashiwada, Yoshiki,Aoshima, Akihiro,Ikeshiro, Yasumasa,Chen, Yuh-Pan,Furukawa, Hiroshi,Itoigawa, Masataka,Fujioka, Toshihiro,Mihashi, Kunihide,Cosentino, L. Mark,Morris-Natschke, Susan L.,Lee, Kuo-Hsiung
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p. 443 - 448
(2007/10/03)
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- SUBSTITUTED MORPHOLINE AND THIOMORPHOLINE DERIVATIVES
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The present invention relates to morpholine and thiomorpholine derivatives of the general formula I or pharmaceutically acceptable salts thereof and their use.
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Page/Page column 58
(2008/06/13)
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- Indole and benzimidazole 15-lipoxygenase inhibitors
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This invention provides indole and benzimidazole 15-lipoxygenase (15-LO) inhibitors of the formula where one of Y1 and Y2 is CH, N, or NH, and the other is R3 includes H, halo. HN2, COOH, alkyl; R4 includes halo, alkyl, and alkoxy; Z is C, CH, or NR5; R5 is H or oxycabonyl; and each X is independently H, alkyl, alkoxy, or halo.
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- Dual probes for the dopamine transporter and σ1 receptors: Novel piperazinyl alkyl-bis(4′-fluorophenyl)amine analogues as potential cocaine-abuse therapeutic agents
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Both dopamine uptake inhibitors and σ1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlyi
- Cao, Jianjing,Kulkarni, Santosh S.,Husbands, Stephen M.,Bowen, Wayne D.,Williams, Wanda,Kopajtic, Theresa,Katz, Jonathan L.,George, Clifford,Newman, Amy Hauck
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p. 2589 - 2598
(2007/10/03)
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- Antiangiogenic and antitumor agents: Design, synthesis, and evaluation of novel 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2,3-d]pyrimidines as inhibitors of receptor tyrosine kinases
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Several different classes of growth factor receptors containing tyrosine kinases (RTK) are directly or indirectly involved in angiogenesis. Inhibition of these RTKs has provided a new paradigm in the treatment of tumors by restricting their growth and metastasis. We have designed, synthesized and evaluated eleven novel 2-amino-4-(3-bromoanilino)-6-substituted benzyl pyrrolo[2,3-d]pyrimidines as the first in a series of RTK inhibitors. These analogues were synthesized from appropriate α-bromomethylbenzyl ketones by cyclocondensation with 2,6-diamino-4-pyrimidone to afford the 2-amino-4-oxo-6-substituted benzyl pyrrolo[2,3-d]pyrimidines. Chlorination of the 4-position followed by displacement with 3-bromoaniline afforded the target compounds. In some instances, the 2-amino moiety of the pyrrolo[2,3-d] pyrimidines was protected prior to the chlorination and displacement followed by deprotection. The compounds were evaluated as inhibitors of vascular endothelial growth factor receptors VEGFR-2 (Flk-1, KDR) and VEGFR-1 (Flt-1); epidermal growth factor receptor (EGFR); and platelet-derived growth factor receptor-β (PDGFR-β). Selected compounds were also evaluated against the growth of A431 cells (which overexpress EGFR) in culture and as inhibitors of angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay. In each evaluation, a known standard compound was used as a comparison. Of the 11 analogues, five were more potent or equipotent as compared to standard compounds against the growth factor receptors. Two analogues showed superior inhibition of A431 cells in culture compared to the standard compounds. Three analogues were equipotent with the standard compound in the CAM assay and four of the analogues were dual inhibitors of RTKs. The structure-activity relationship for inhibition of different RTKs was quite distinct and different, and for VEGFR-2 and EGFR diametrically opposite. The inhibitory data against the RTKs in this study demonstrates that variation of the substituent(s) in the benzyl ring of these 2-amino-4-anilino 6-benzyl pyrrolo[2,3-d]pyrimidines does indeed control both the potency and specificity of inhibitory activity against RTKs.
- Gangjee, Aleem,Yang, Jie,Ihnat, Michael A.,Kamat, Shekhar
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p. 5155 - 5170
(2007/10/03)
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- Synthesis, selective aldose reductase inhibitory profile and antihyperglycaemic potential of certain parabanic acid derivatives
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Synthesis and aldose reductase inhibitory profile of certain parabanic acid derivatives 1a-p is described. Also, the antihyperglycaemic potential of these compounds was studied. The most active inhibitors in this series were compounds 1 g, 1p, and 1o which showed inhibitory activity, 36.6, 90 and 91% respectively, at concentration 1 × 10-4. Their IC50 were 2 × 10-6, 7.5 × 10-8 and 5 × 10-8, respectively. Compound 1o exhibited pronounced antihyperglycaemic effect.
- Nabil Aboul-Enein,El-Azzounya,Maklad,Attia,Wiese
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p. 329 - 350
(2007/10/03)
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- Carboxy substituted acylic carboxamide derivatives
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The present invention relates to novel carboxy substituted acyclic carboxamide derivatives of formula (1)): STR1and stereoisomers and pharmaceutically acceptable salts thereof and their use as tachykinin receptor antagonists. Such antagonists are useful in the treatment of tachykinin-mediated diseases and conditions disclosed herein including: asthma, cough, and bronchitis.
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- Quinolones as gonadotropin releasing hormone (GnRH) antagonists: Simultaneous optimization of the C(3)-aryl and C(6)-substituents
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A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Young, Jonathan R.,Huang, Song X.,Chen, Irene,Walsh, Thomas F.,DeVita, Robert J.,Wyvratt Jr., Matthew J.,Goulet, Mark T.,Ren, Ning,Lo, Jane,Yang, Yi Tien,Yudkovitz, Joel B.,Cheng, Kang,Smith, Roy G.
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p. 1723 - 1727
(2007/10/03)
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- Design and Synthesis of Naphthalenic Derivatives as Potential Inhibitors of Hydroxyindole-O-methyltransferase
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Hydroxyindole-O-methyltransferase is an enzyme that catalyses the last step of melatonin biosynthesis. The objective of this work was to design and synthesize potential inhibitors of hydroxyindole-O-methyltransferase. Applying bioisosteric principles to the indolic nucleus, we considered the synthesis of naphthalenic derivatives and varied the nature of substituents at position 7 and the amide group. We also replaced the ethylene moiety at position 1 by its lower and higher homologues, and synthesized C4 retroamides. Of the compounds synthesized, N-[2-(7-naphth-1-yl)]phenylacetamide was the best inhibitor of hydroxyindole-O-methyltransferase (77 percent inhibition at a concentration of 10-4 M). Moreover, most of naphthols behaved as enzyme substrates. The ethyl side chain at position 1 was an essential element for optimal biological activity.
- Picard, I. le,Depreux, P.,Lesieur, I.,Delagrange, P.,Bennejean, C.,Renard, P.,Voisin, P.
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p. 183 - 188
(2007/10/03)
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- Kappa opioid receptor agonists
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The invention provides certain amino acid conjugates of substituted 2-phenyl-N-[1-(phenyl)-2-(1-heterocycloalkyl- or heterocycloaryl-)ethyl]acetamides useful for selectively agonizing kappa opioid receptors in mammalian tissue.
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- Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters
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Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((±)-19, PG9) also has remarkable cognition- enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.
- Gualtieri,Conti,Dei,Giovannoni,Nannucci,Romanelli,Scapecchi,Teodori,Fanfani,Ghelardini,Giotti,Bartolini
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p. 1704 - 1711
(2007/10/02)
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- κ Opioid Receptor Selective Affinity Labels: Electrophilic Benzeneacetamides as κ-Selective Opioid Antagonists
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2-(3,4-Dichlorophenyl)-N-methyl-N-acetamides 3-6 were synthesized as κ-selective affinity labels and evaluated for opioid activity.In smooth muscle preparations, the non-electrophilic parent compound
- Chang, An-Chih,Takemori, Akira E.,Ojala, William H.,Gleason, William B.,Portoghese, Philip S.
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p. 4490 - 4498
(2007/10/02)
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- Diamine compounds
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Compounds of the general formula I STR1 wherein R1 represents a halophenyl, dihalophenyl, nitrophenyl, cyanophenyl or trifluoromethylphenyl group; X represents a single bond, --CH2 --, --OCH2 --, SCH2, --S(O)--C
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- Heteroannulation process
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A heteroannulation process for preparing piperidones and tetrahydropyridones by reacting an appropriately substituted enamine with an acryloyl derivative wherein a leaving group occupies the carbonyl; a process for cleaving a 1-phenylethyl group from an a
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- Synthesis and in vitro evaluation of 5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indoles: High-affinity ligands for the N,N'-di-o- tolylguanidine-labeled σ binding site
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A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclo[b]indoles substituted at the 5 and/or 11 positions was synthesized from tropinone. Affinity for σ binding sites was determined using [3H]-N,N'-di-o-tolylguanidine ([3H]DTG) and [sup
- Mewshaw,Sherrill,Mathew,Kaiser,Bailey,Karbon
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p. 343 - 352
(2007/10/02)
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- THE PRODUCTION OF 2,4-DICHLOROPHENACYL CHLORIDE
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The acylation of a mixture of dichlorobenzene isomers by chloroacetyl chloride in the presence of anhydrous aluminum chloride leads to the selective formation of 2,4-dichlorophenacyl chloride.
- Rekhter, M. A.,Reinbol'd, A. I.,Krimer, M. Z.
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p. 1152 - 1153
(2007/10/02)
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- Selective Reversible and Irreversible Ligands for the κ Opioid Receptor
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(+/-)-(5β,7α,8β)-3,4-Dichloro-N-methyl-N-dec-7-yl>benzeneacetamide (14) and its (5α,7α,8β) diastereomer 15 have been synthesized from 1,4-cyclohexanedione monoethylene ketal (1) in 10 steps.Compound 14,
- Cheng, Chen-Yu,Wu, Shou-Chien,Hsin, Ling-Wei,Tam, S. William
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p. 2243 - 2247
(2007/10/02)
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- (1S)-1-(Aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: Members of a novel class of very potent κ opioid analgesics
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The synthesis and structure-activity relationship (SAR) of a novel class of κ opioid analgesics, 1-(amino-methyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60° was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of κ receptor selectivity was a feature of this novel class of antinociceptive agents (μ/κ ratio from 44 to 950 according to the nature of the basic moiety). A SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 μM/kg sc) and κ ligands (K(i)(κ) ca. 0.20 nM) identified so far.
- Vecchietti,Clarke,Colle,Giardina,Petrone,Sbacchi
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p. 2624 - 2633
(2007/10/02)
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- (2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: Novel, highly selective κ opioid analgesics
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This paper describes the synthesis and structure-activity relationships as κ opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives (8). The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60°, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and κ affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl) piperidine hydrochloride (14) and (2S)-1-[[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1- ylmethyl)piperidine hydrochloride (21) are the most κ/μ selective (respectively 6500:1 and 4100:1) and among the most potent (K(i) κ 0.24 and 0.57 nM, respectively) κ ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard κ ligand U-50488.
- Vecchietti,Giordani,Giardina,Colle,Clarke
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p. 397 - 403
(2007/10/02)
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- Diamine compounds
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Compounds of the general formula I wherein R1 represents an optionally substituted C6-10 aryl group, or R1 represents an optionally substituted 5- or 6--membered heterocyclic moiety;, X represents a single bond, -CH2-, -OCH2/su
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