- Novel monoacylglycerol lipase inhibitor as well as preparation method and application thereof
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The invention discloses a novel monoacylglycerol lipase inhibitor as well as a preparation method and application thereof. Specifically, the invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated derivative thereof. Experimental results show that the compound provided by the invention can effectively inhibit MAGL activity, can beused for preparing an MAGL inhibitor and preparing medicines for preventing and/or treating diseases (including endometrial cancer, colorectal cancer, liver cancer, breast cancer, ovarian cancer, neurodegenerative diseases and the like) related to abnormal MAGL activity, and has a wide application prospect.
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Paragraph 0264-0266
(2021/02/10)
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- Synthesis and Antifungal Activity of New N-Aryl-2-(2-hydroxyphenylamino)ethylenediamine Derivatives
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Abstract: In this study, a series of new N-aryl-2-(2-hydroxyphenylamino)ethylenediamine derivatives has beendesigned, synthesized and evaluated for antifungal activity against six selectedspecies of phytopathogenic fungi. Among the products, the most potent compoundhave demonstrated 97.7% inhibitory activity against S.sclerotiorum at the concentration of 50 μg/mL, which is higherthan that of the positive control chlorothalonil.
- Gao, Han,Wan, Yichao,Tan, Yuhuan,Luo, Xi,Li, Lin
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p. 122 - 127
(2021/02/21)
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- Synthesis and Cytotoxic Evaluation of Some New 1,2,3-Triazole Linked 2-Imino-4-(Trifuoromethyl)-Thiazolidin-4-ol Derivatives
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A new series of 1,2,3-triazole tagged 2-imino-4-(trifluoromethyl)thiazolidinol derivatives was synthesized through click chemistry under Sharpless conditions and evaluated for anticancer activity against human monocytic leukemia (U937), human breast adeno
- Appalanaidu, K.,Dadmal, Tulshiram L.,Kumbhare, Ravindra M.,Pamanji, R.,Rao, J. Venkateswara,Reddy, Prathyusha J.,Velatooru, L. R.
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- 1,3,4,9-TETRAHYDRO-2H-PYRIDO[3,4-B]INDOLE DERIVATIVE COMPOUNDS AND USES THEREOF
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The present invention relates to 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole derivative compounds and uses thereof. In particular, compounds of the invention have antibacterial activity and/or are capable of re-sensitizing methicillin-resistant Staphylococcus aureus to a P-lactam antibiotic or a combination of a P-lactam antibiotic and a P-lactamase inhibitor. The present invention also relates to a method for producing and using said compounds.
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Paragraph 0134-0315; 0137
(2020/03/05)
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- Design, synthesis of novel (Z)-2-(3-(4-((3-benzyl-2,4-dioxothiazolidin-5-ylidene)methyl)-1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamide derivatives: Evaluation of cytotoxic activity and molecular docking studies
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In an attempt to discover potential cytotoxic agents, a series of novel (Z)-2-(3-(4-((3-benzyl-2,4-dioxothiazolidin-5-ylidene)methyl)-1-phenyl-1H-pyrazol-3-yl) phenoxy)-N-arylacetamide derivatives 11a-n were synthesized in varied steps with acceptable reaction procedures with good yields and characterized by 1H NMR, 13C NMR, IR and ESI-MS spectra. All the novel synthesized derivatives were assessed for their cytotoxic activity against human breast cell line (MCF-7) with different concentration of 0.625 μM, 1.25 μM, 2.5 μM, 5 μM and 10 μM respectively. Biological evaluation assay results were displayed in terms of percentage of cell viability reduction and IC50 values. Most of the screened derivatives demonstrated moderate to promising cytotoxic activity. Some of the derivatives, particularly compound 11d and 11n have shown promising cytotoxic activity with IC50 values 0.604 μM and 0.665 μM compared to standard drug cisplatin and compounds 11a, 11e and 11g also have shown considerable cytotoxic activity and the rest of the derivatives have shown moderate activity. Furthermore, molecular docking calculations and ADME properties of the synthesized molecules are in effective compliance with the cytotoxic evaluation results.
- Kolluri, Prashanth Kumar,Gurrapu, Nirmala,Subhashini,Putta, Shravani,Singh, Surya Sathyanarayana,Vani, Tamalapakula,Manga, Vijjulatha
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- Synthesis, anticancer, and computational studies of 1, 3, 4-oxadiazole-purine derivatives
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Theophylline-7-acetic acid (acefylline) (3) and its derivatives are pharmacologically active compounds and generally recognized as bronchodilators for the treatment of respiratory diseases like acute asthma for over 70 years. In this article, synthesis of
- Faisal, Shahla,Kamal, Shagufta,Parveen, Bushra,Rasool, Nasir,Rasul, Azhar,Raza, Zohaib,Shahzadi, Irum,Zahid, Faisal M.,Zahoor, Ameer F.,Zia-ur-Rehman, Muhammad
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p. 2782 - 2794
(2020/04/16)
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- N-heterocycles scaffolds as quorum sensing inhibitors. Design, synthesis, biological and docking studies
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Quorum sensing is a communication system among bacteria to sense the proper time to express their virulence factors. Quorum sensing inhibition is a therapeutic strategy to block bacterial mechanisms of virulence. The aim of this study was to synthesize and evaluate new bioisosteres of N-acyl homoserine lactones as Quorum sensing inhibitors in Chromobacterium violaceum CV026 by quantifying the specific production of violacein. Five series of compounds with different heterocyclic scaffolds were synthesized in good yields: thiazoles, 16a–c, thiazolines 17a–c, benzimidazoles 18a–c, pyridines 19a–c and imidazolines 32a–c. All 15 compounds showed activity as Quorum sensing inhibitors except 16a. Compounds 16b, 17a–c, 18a, 18c, 19c and 32b exhibited activity at concentrations of 10 μM and 100 μM, highlighting the activity of benzimidazole 18a (IC50 = 36.67 μM) and 32b (IC50 = 85.03 μM). Pyridine 19c displayed the best quorum sensing inhibition activity (IC50 = 9.66 μM). Molecular docking simulations were conducted for all test compounds on the Chromobacterium violaceum CviR protein to gain insight into the process of quorum sensing inhibition. The in-silico data reveal that all 15 the compounds have higher affinity for the protein than the native AHL ligand (1). A strong correlation was found between the theoretical and experimental results.
- Fuentes-Gutiérrez, Alfredo,Curiel-Quesada, Everardo,Correa-Basurto, José,Martínez-Mu?oz, Alberto,Reyes-Arellano, Alicia
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- Substituted Pyridazin-3(2 H)-ones as Highly Potent and Biased Formyl Peptide Receptor Agonists
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Herein we describe the development of a focused series of functionalized pyridazin-3(2H)-one-based formyl peptide receptor (FPR) agonists that demonstrate high potency and biased agonism. The compounds described demonstrated biased activation of prosurvival signaling, ERK1/2 phosphorylation, through diminution of the detrimental FPR1/2-mediated intracellular calcium (Cai2+) mobilization. Compound 50 showed an EC50 of 0.083 μM for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Cai2+ mobilization at the hFPR1.
- Deora, Girdhar Singh,Qin, Cheng Xue,Vecchio, Elizabeth A.,Debono, Aaron J.,Priebbenow, Daniel L.,Brady, Ryan M.,Beveridge, Julia,Teguh, Silvia C.,Deo, Minh,May, Lauren T.,Krippner, Guy,Ritchie, Rebecca H.,Baell, Jonathan B.
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supporting information
p. 5242 - 5248
(2019/05/28)
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- Design, Synthesis, Antimicrobial Evaluation, and Laccase Catalysis Effect of Novel Benzofuran–Oxadiazole and Benzofuran–Triazole Hybrids
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Novel structural hybrids of benzofuran–oxadiazole and benzofuran–triazole have been synthesized and evaluated for their potential against Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. The excellent antibiotic activity was shown by compou
- Faiz, Sadia,Zahoor, Ameer Fawad,Ajmal, Muhammad,Kamal, Shagufta,Ahmad, Sajjad,Abdelgawad, Abdelrahman M.,Elnaggar, Mehrez E.
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p. 2839 - 2852
(2019/11/03)
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- 3-Aminomethyl pyridine chalcone derivatives: Design, synthesis, DNA binding and cytotoxic studies
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Herein we report design, synthesis, and anticancer activity of compounds 6a–h and 11a–j. Compounds 6a–f were designed based on 3-aminomethyl pyridine attached to different acetamide derivatives and in compounds 6g–h it was attached to coumarin moiety. Coumarin containing compounds 6g–h showed very poor anticancer activity against both A549 (Lungs cancer cell line), and MCF-7 (Breast cancer cell line) cell lines in MTT assay. Compounds 11a–j were designed as derivatives of 3-aminomethyl pyridine and 4-amino chalcones. A series of chalcone derivatives of 3-aminomethyl pyridine 11a–j have been synthesized and screened for their in vitro anticancer activity and DNA binding affinity. Most of the compounds showed very good antimitotic activity against A549 cell line as compared to fluorouracil. Compounds 11g and 11i were selected for DNA-binding studies as they showed excellent activity against cancer cell lines in MTT assay. CT-DNA binding affinity of compounds 11g and 11i have been investigated by UV based DNA titration and fluorescence emission study against DNA-EtBr complex. Interestingly, compound 11i has displayed excellent antiproliferative activity, with IC50 0.0067?±?0.0002?μm, against MCF-7 cell line. Compound 11i has been studied for its cytotoxicity using MTT, LDH, as well as EtBr/AO assay and was found to induce apoptosis in the cancerous cell line.
- Durgapal, Sunil Dutt,Soni, Rina,Umar, Shweta,Suresh, Balakrishnan,Soman, Shubhangi S.
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p. 1279 - 1287
(2018/06/29)
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- 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains
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2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.
- Pissinate, Kenia,Villela, Anne Drumond,Rodrigues, Valnês,Giacobbo, Bruno Couto,Grams, Estêv?o Silveira,Abbadi, Bruno Lopes,Trindade, Rogério Valim,Roesler Nery, Laura,Bonan, Carla Denise,Back, Davi Fernando,Campos, Maria Martha,Basso, Luiz Augusto,Santos, Diógenes Santiago,Machado, Pablo
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supporting information
p. 235 - 239
(2016/03/22)
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- Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives
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Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC50 values in the 80–250 nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.
- Leung, Euphemia,Pilkington, Lisa I.,van Rensburg, Michelle,Jeon, Chae Yeon,Song, Mirae,Arabshahi, Homayon J.,De Zoysa, Gayan Heruka,Sarojini, Vijayalekshmi,Denny, William A.,Reynisson, Jóhannes,Barker, David
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supporting information
p. 1142 - 1154
(2019/05/24)
-
- Synthesis and evaluation of thiazolyl-1H-benzo[d]imidazole inhibitors of Mycobacterium tuberculosis inosine monophosphate dehydrogenase
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Using an orthologue-based design approach, we synthesized and assayed a series of thiazolyl-1H-benzo[d]imidazole derivatives as inhibitors of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase (MtIMPDH). From these experiments, a benzo[d] imidazole compound was described to inhibit the enzyme in the low micromolar range (KiIMP = 0.55 ± 0.02 μM), which places this compound among the most potent in vitro MtIMPDH inhibitors developed to date. In addition, steady-state kinetic measurements and docking simulations were employed to determine its inhibition and interaction modes. The results described herein may be useful for the design and development of novel alternative therapeutics for tuberculosis that target MtIMPDH, a predicted to be essential (for optimal in vitro bacillus growth), druggable and assayable molecular target.
- Pissinate, Kenia,Rostirolla, Diana Carolina,Pinheiro, Laura Miranda,Suryadevara, Priyanka,Yogeeswari, Perumal,Sriram, Dharmarajan,Basso, Luiz Augusto,Machado, Pablo,Santos, Diógenes Santiago
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p. 1357 - 1366
(2015/07/15)
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- Synthesis, in vitro evaluation and cocrystal structure of 4-oxo-[1]benzopyrano[4,3-c]pyrazole cryptosporidium parvum inosine 5′-monophosphate dehydrogenase (Cp IMPDH) inhibitors
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Cryptosporidium inosine 5′-monophosphate dehydrogenase (CpIMPDH) has emerged as a therapeutic target for treating Cryptosporidium parasites because it catalyzes a critical step in guanine nucleotide biosynthesis. A 4-oxo-[1]benzopyrano[4,3-c]pyrazole derivative was identified as a moderately potent (IC50 = 1.5 μM) inhibitor of CpIMPDH. We report a SAR study for this compound series resulting in 8k (IC50 = 20 ± 4 nM). In addition, an X-ray crystal structure of CpIMPDH·IMP·8k is also presented.
- Sun, Zhuming,Khan, Jihan,Makowska-Grzyska, Magdalena,Zhang, Minjia,Cho, Joon Hyung,Suebsuwong, Chalada,Vo, Pascal,Gollapalli, Deviprasad R.,Kim, Youngchang,Joachimiak, Andrzej,Hedstrom, Lizbeth,Cuny, Gregory D.
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supporting information
p. 10544 - 10550
(2015/02/19)
-
- The effect of a thieno[2,3-b]pyridine PLC-γ inhibitor on the proliferation, morphology, migration and cell cycle of breast cancer cells
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3-Amino-N-(3-chlorophenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b] quinoline-2-carboxamide (compound 1) is a putative phosphoinositide specific-phospholipase C-γ (PLC-γ) enzyme inhibitor. This enzyme is a plausible anticancer target linked to cell motility, important for the invasion and dissemination of tumour cells. In this work it is shown that IC50 values of compound 1 are in the low nanomolar range against a host of breast cancer cell lines as a consequence of anti-proliferative activity. These results correlate well with previously published results (Feng et al., Eur. Med. Chem., 54, 2012, 463-469) on tumour cell viability confirming the efficacy of compound 1. Flow cytometry experiments revealed that compound 1 arrests the cell cycle in the G2/M phases. Furthermore, the morphology and cell migration for the MDA-MB-231 breast cancer cell line are severely affected by administration of compound 1, which fits the hypothesis of PLC-γ inhibition. Finally, a detailed docking study against PLC reveals that the side chains of the amino acids His356, Glu341, Arg549 and Lys438 are involved in hydrogen bonding with ligand 1 as well as a lipophilic pocket is occupied by the phenyl moiety. The results presented in this study are particularly interesting because compound 1 affects triple-negative breast cancer cells, which are difficult to treat in the clinic and are in a dire need for an effective targeted therapy. We believe that compound 1 and its thieno[2,3-b]pyridine derivatives demonstrate that such a therapy can be developed.
- Leung, Euphemia,Hung, Joy M.,Barker, David,Reynisson, Johannes
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-
- Synthesis and cytotoxicity of thieno[2,3-b]pyridine and furo[2,3-b]pyridine derivatives
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Forty seven thieno[2,3-b]pyridines-2-carboxamides, furo[2,3-b]pyridines-2-carboxamides and tetrahydrothieno[2,3-b]quinolones-2-carboxamides derivatives were synthesized and tested for their antiproliferative activity against the NCI-60 cell lines. The 5-keto-tetrahydrothieno[2,3-b]quinolones-2-carboxamides (series 17) were found to have the greatest activity, with the compound containing a 3-methoxyphenylcarboxamide (compound 17d) being the most active, with GI50values in the low nanomolar range against a range of cell lines, in particular the melanoma cell line MDA-MD-435 (GI50- 23 nM) and the breast cancer cell line MDA-MB-468 (GI50- 46 nM). Molecular modelling of series 17 against phosphoinositide specific-phospholipase C reveals that the side chains of the amino acids His356, Glu341, Arg549 and Lys438 are involved in hydrogen bonding with the ligands as well as a lipophilic pocket is occupied by the phenyl carboxamide moiety.
- Hung, Joy M.,Arabshahi, Homayon J.,Leung, Euphemia,Reynisson, Jóhannes,Barker, David
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p. 420 - 437
(2015/02/19)
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- Synthesis of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives and their cytotoxic activity
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A series of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives 3 and 4 were prepared respectively starting from 6-phenyl-4-(trifluoromethyl)- 1H-pyrazolo[3,4-b]pyridin-3-amine 1 via selective N-propargylation, followed by reaction with divers
- Kurumurthy, Chavva,Veeraswamy, Banda,Sambasiva Rao, Pillalamarri,Santhosh Kumar, Gautham,Shanthan Rao, Pamulaparthy,Loka Reddy, Velaturu,Venkateswara Rao, Janapala,Narsaiah, Banda
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p. 746 - 749
(2014/02/14)
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- Synthesis and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold
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In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B-NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B-NS3 protease inhibitor with a 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor (1a24, IC50=3.4±0.2μM) of the WNV NS2B-NS3 protease. Molecular docking of 1a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.
- Samanta, Sanjay,Lim, Ting Liang,Lam, Yulin
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supporting information
p. 994 - 1001
(2013/07/27)
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- Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH
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Cryptosporidium parasites are important waterborne pathogens of both humans and animals. The Cryptosporidium parvum and Cryptosporidium hominis genomes indicate that the only route to guanine nucleotides is via inosine 5′-monophosphate dehydrogenase (IMPDH). Thus the inhibition of the parasite IMPDH presents a potential strategy for treating Cryptosporidium infections. A selective benzimidazole-based inhibitor of C. parvum IMPDH (CpIMPDH) was previously identified in a high throughput screen. Here we report a structure-activity relationship study of benzimidazole-based compounds that resulted in potent and selective inhibitors of CpIMPDH. Several compounds display potent antiparasitic activity in vitro.
- Kirubakaran, Sivapriya,Gorla, Suresh Kumar,Sharling, Lisa,Zhang, Minjia,Liu, Xiaoping,Ray, Soumya S.,MacPherson, Iain S.,Striepen, Boris,Hedstrom, Lizbeth,Cuny, Gregory D.
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scheme or table
p. 1985 - 1988
(2012/04/05)
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- Design, synthesis and biological evaluation of hydroxamic acid derivatives as potential high density lipoprotein (HDL) receptor CLA-1 up-regulating agents
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Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) were reported in our recent publication as novel human high density lipoprotein (HDL) receptor CD36 and Lysosomal integral membrane protein-II Analogous-1 (CLA-1) up-regulators. As part of a
- Chen, Xiaofang,Wang, Li,Du, Yu,Wu, Yanbin,Jia, Xiaojian,Yang, Yuan,Hong, Bin
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experimental part
p. 9178 - 9193
(2012/01/12)
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- SPIRO-CONDENSED IMIDAZOLONE DERIVATIVES INHIBITING THE GLYCINE TRANSPORTER
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Compounds of formula (I) and salts thereof are provided: formula (I), wherein the groups are as defined in the specification. Uses of the compounds as medicaments, and in the manufacture of medicament for treating neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder are also disclosed. The invention further comprises processes to make these compounds and pharmaceutical formulations thereof.
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Page/Page column 47
(2009/04/25)
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- Novel macrolides and ketolides having antimicrobial activity
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The present invention provides compounds having antimicrobial activity for preventing and treating diseases caused by microbial infections. Thus, the present invention relates to novel semi-synthetic 11,12-γ lactone macrolides and ketolides having antimicrobial activity, processes for making compounds as well as pharmaceutical compositions containing said compounds as active ingredients and methods of treating microbial infections with the compounds.
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Page/Page column 44
(2009/10/06)
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- NOVEL MACROLIDES AND KETOLIDES HAVING ANTIMICROBIAL ACTIVITY
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The present invention provides compounds having antimicrobial activity for preventing and treating diseases caused by microbial infections. Thus, the present invention relates to novel ? semi-synthetic 11,12-γ lactone macrolides and ketolides having antimicrobial activity, processes for making compounds as well as pharmaceutical compositions containing said compounds as active ingredients and methods of treating microbial infections with the compounds.
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Page/Page column 82
(2008/06/13)
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- 1,3-Dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists
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A new series of 1,3-dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives has been identified as potent A2B adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A2B, A1, A2A, and A3 adenosine receptors. N-(4-chloro-phenyl)-2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl] (11c) showed a high affinity for the human A2B adenosine receptor Ki = 7 nM and good selectivity (A1, A2A, A3/A2B > 140). Synthesis and SAR of this novel class of compounds is presented herein.
- Tabrizi, Mojgan Aghazadeh,Baraldi, Pier Giovanni,Preti, Delia,Romagnoli, Romeo,Saponaro, Giulia,Baraldi, Stefania,Moorman, Allan R.,Zaid, Abdel Naser,Varani, Katia,Borea, Pier Andrea
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p. 2419 - 2430
(2008/09/21)
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- Lead discovery and optimization of T-type calcium channel blockers
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A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with α1G and α1H clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC50 values than Mibefradil.
- Park, Jung Hwan,Choi, Jin Kyu,Lee, Eunjung,Lee, Jae Kyun,Rhim, Hyewhon,Seo, Seon Hee,Kim, Yoonjee,Doddareddy, Munikumar Reddy,Pae, Ae Nim,Kang, Jahyo,Roh, Eun Joo
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p. 1409 - 1419
(2008/02/11)
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- Discovery of 3-methyl-N-(1-oxy-3′,4′,5′,6′- tetrahydro-2′H-[2,4′-bipyridine]-1′-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction
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The goal of this study was to identify a structurally distinct D4-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
- Patel, Meena V.,Kolasa, Teodozyj,Mortell, Kathleen,Matulenko, Mark A.,Hakeem, Ahmed A.,Rohde, Jeffrey J.,Nelson, Sherry L.,Cowart, Marlon D.,Nakane, Masaki,Miller, Loan N.,Uchic, Marie E.,Terranova, Marc A.,El-Kouhen, Odile F.,Donnelly-Roberts, Diana L.,Namovic, Marian T.,Hollingsworth, Peter R.,Chang, Renjie,Martino, Brenda R.,Wetter, Jill M.,Marsh, Kennan C.,Martin, Ruth,Darbyshire, John F.,Gintant, Gary,Hsieh, Gin C.,Moreland, Robert B.,Sullivan, James P.,Brioni, Jorge D.,Stewart, Andrew O.
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p. 7450 - 7465
(2007/10/03)
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- Acetamides and benzamides that are useful in treating sexual dysfunction
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The present invention relates to the use of compounds of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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- Acetamides and benzamides that are useful in treating sexual dysfunction
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The present invention relates to the use of compounds of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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- Inhibitors of farnesyl-protein transferase
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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