- Novel TRPV1 antagonism/FAAH inhibition double-target drug, and preparation method and application thereof
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The invention discloses a novel TRPV1 antagonism/FAAH inhibition double-target drug, and a preparation method and application thereof. The TRPV1 antagonism/FAAH inhibition double-target drug or a pharmaceutically acceptable salt thereof has a structural g
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Paragraph 0048-0051; 0067; 0069-0070
(2021/08/11)
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- Novel cilengitide-based cyclic RGD peptides as αvβ3 integrin inhibitors
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In this letter, we report a series of five new RGD-containing cyclic peptides as potent inhibitors to αvβ3 integrin protein. We have incorporated various unnatural lipophilic amino acids into the cyclic RGD framework of cilengitide, which is selective for αvβ3 integrin. All the newly synthesized cyclic peptides were evaluated in vitro solid phase binding assay and investigated for their binding behaviour towards integrin subtypes. All the cyclic peptides were synthesized in excellent yield following solution-phase coupling strategy. The cyclic RGD peptides 1a-e exhibited IC50 of 9.9, 5.5, 72, 11 and 3.3 nM, respectively, towards αvβ3 integrin protein. This finding offers further opportunities for the introduction unusual amino acids into the cyclic peptide framework of cilengitide.
- Dangi, Abha,Marelli, Udaya Kiran,Meena, Chhuttan L.,Reichart, Florian,Sanjayan, Gangadhar J.,Singh, Dharmendra,Zahler, Stefan,Weinmüller, Michael
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supporting information
(2020/02/28)
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- Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1
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ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide) and compound 2 (1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase activity. Compound 3 (4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid) allosterically activates ERAP1's hydrolysis of fluorogenic and chromogenic amino acid substrates but competitively inhibits its activity toward a nonamer peptide representative of physiological substrates. Compounds 2 and 3 inhibit antigen presentation in a cellular assay. Compound 3 displays higher potency for an ERAP1 variant associated with increased risk of autoimmune disease. These inhibitors provide mechanistic insights into the determinants of specificity for ERAP1, ERAP2, and IRAP and offer a new therapeutic approach of specifically inhibiting ERAP1 activity in vivo.
- Maben, Zachary,Arya, Richa,Rane, Digamber,An, W. Frank,Metkar, Shailesh,Hickey, Marc,Bender, Samantha,Ali, Akbar,Nguyen, Tina T.,Evnouchidou, Irini,Schilling, Roger,Stratikos, Efstratios,Golden, Jennifer,Stern, Lawrence J.
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p. 103 - 121
(2020/02/20)
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- Cathepsin K inhibitor and application thereof
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The invention relates to a cathepsin K inhibitor and an application thereof, and specifically, relates to a compound and a drug composition thereof used for treating or preventing cathepsin dependence diseases, and the compound and the composition containing the compound can be used as a bone resorption inhibitor to treat relevant diseases. The cathepsin includes but is not limited to cathepsin K.
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Paragraph 0168; 0169
(2017/08/30)
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- The synthesis of α,α-disubstituted α-amino acids via ichikawa rearrangement
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An approach to α,α-disubstituted α-amino acids is reported. The key step is allyl cyanate-to-isocyanate rearrangement. As demonstrated, the resultant allyl isocyanates can be directly trapped with various nucleophiles, for instance, alcohols, amines, and organometallic reagents, to provide a broad range of N-functionalized allylamines. The developed method has been successfully applied in the synthesis of two bioactive peptides: 2-aminoadamantane-2-carboxylic acid derived P2X7-evoked glutamate release inhibitor and 4-amino-tetrahydropyranyl-4-carboxylic acid derived dipeptide GSK-2793660, which is currently in clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, noncystic fibrosis bronchiectasis, ANCA-associated vasculitis and bronchiectasis.
- Szczes?niak, Piotr,Pieczykolan, Micha?,Stecko, Sebastian
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p. 1057 - 1074
(2016/02/19)
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- C-3 NOVEL TRITERPENONE WITH C-28 REVERSE AMIDE DERIVATIVES AS HIV INHIBITORS
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Formula (I) The invention relates to C-3 novel triterpenone with C-28 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 59; 60
(2016/11/21)
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- Silicon Amine Reagents for the Photocatalytic Synthesis of Piperazines from Aldehydes and Ketones
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Silicon amine protocol (SLAP) reagents for photocatalytic cross-coupling with aldehydes and ketones to form N-unprotected piperazines have been developed. This blue light promoted process tolerates a wide range of heteroaromatic, aromatic, and aliphatic aldehydes and structurally and stereochemically complex SLAP reagents. It provides a tin-free alternative to SnAP (tin amine protocol) reagents for the synthesis of substituted piperazines.
- Hsieh, Sheng-Ying,Bode, Jeffrey W.
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supporting information
p. 2098 - 2101
(2016/06/01)
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- Synthesis and Anticonvulsant Activity of Substituted-1,3-diazaspiro[4.5]decan-4-ones
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A series of novel spiroimidazolidinone derivatives 6a-d and 8a-x were synthesized and biologically evaluated for their anticonvulsant activity in the maximal electroshock seizure (MES) assay and the subcutaneous pentylenetetrazole (scPTZ) screening test. Compound 8w was the most active derivative in the scPTZ screening test with an ED50 value by about 5- and 83.6-fold lower than those of phenobarbital and ethosuximide as reference drugs, respectively. Most of the tested compounds exhibited moderate to weak activity in the MES screen test, except for 8a which displayed 100% protection at 0.09 mmol/kg. Moreover, all the test compounds did not show any minimal motor impairment in the neurotoxicity test.
- Aboul-Enein, Mohamed Nabil,El-Azzouny, Aida Abdel Sattar,Saleh, Ola Ahmed,Amin, Kamilia Mahmoud,Maklad, Yousreya Ali,Hassan, Rasha Mohamed
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p. 575 - 588
(2015/08/11)
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- PEPTIDYL NITRILCOMPOUNDS AS PEPTIDASE INHIBITORS
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The invention relates to compounds of Formula (II) and their use in theraphy as peptidase inhibitors.
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Page/Page column 114
(2012/09/22)
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- New cathepsin inhibitors to explore the fluorophilic properties of the S2 pocket of cathepsin B: Design, synthesis, and biological evaluation
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Fluor-in or out? Based on β,β-difluorinated cycloaliphatic amino acids, a library of new dipeptide nitriles was evaluated as human cathepsin inhibitors. The orientation of the fluorinated face relative to the protein structure of cathepsin B was elucidated by molecular modeling and NMR studies (see figure). For (R)-configured eutomers, the fluorine atoms are directed to the S2 pocket, whereas in (S)-configured distomers, the fluorinated face is solvent-exposed.
- Fustero, Santos,Rodrigo, Vanessa,Sanchez-Rosello, Maria,Del Pozo, Carlos,Timoneda, Joaquin,Frizler, Maxim,Sisay, Mihiret T.,Bajorath, Juergen,Calle, Luis P.,Canada, F. Javier,Jimenez-Barbero, Jesas,Guetschow, Michael
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supporting information; scheme or table
p. 5256 - 5260
(2011/06/24)
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- Facing the gem-dialkyl effect in enzyme inhibitor design: Preparation of homocycloleucine-based azadipeptide nitriles
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A tough nut to crack: In contrast to azadipeptide nitriles containing a P2 leucine residue, the synthesis of the corresponding homocycloleucine-based inhibitors was more difficult; possibly due to the gem-dialkyl effect. A synthetic route to the first hom
- Frizler, Maxim,Lohr, Friederike,Luelsdorff, Michael,Guetschow, Michael
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supporting information; experimental part
p. 11419 - 11423
(2011/11/29)
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- Stieglitz rearrangement of N,N-dichloro-β,β-disubstituted taurines under mild aqueous conditions
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New topical anti-infectives comprised of N,N-dichloro-β,β-disubstituted taurines [Tetrahedron Lett. 2008, 49, 2193; Biorg. Med. Chem. Lett. 2009, 19, 196] have been examined for structure-stability relationships (SSR) based upon various alkyl, heteroalkyl
- Shiau, Timothy P.,Houchin, Ashley,Nair, Satheesh,Xu, Ping,Low, Eddy,Najafi, Ramin (Ron),Jain, Rakesh
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scheme or table
p. 1110 - 1114
(2009/08/07)
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- DIARYL-CYCLYLALKYL DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
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Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted N-type and/or T-type calcium channel activity are disclosed. Specifically, a series of compounds of substituted or unsubstituted N-cyclylalkyl-diphenylpropanamide derivatives as shown in formula (1).
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- 1,3-Dihydro-2H-Indole-2-One Compound and Pyrrolidine-2-One Compound Fused With Aromatic Heterocycle
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It is intended to provide a drug which is efficacious against pathological conditions relating to arginine-vasopressin V1b receptor. More particularly speaking, it is intended to provide a drug which has a therapeutic or preventive effect on depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, digestive diseases, drug addiction, epilepsy, brain infarction, brain ischemia, brain edema, head injury, inflammation, immune diseases, alopecia and so on. As the results of intensive studies, a novel 1,3-dihydro-2H-indol-2-one compound and a pyrrolidin-2-one compound fused with a heteroaromatic ring, which are highly selective antagonists of arginine-vasopressin V1b receptor, have high metabolic stabilities and show favorable brain penetration and high plasma concentrations, are found, thereby achieving the above objective.
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Page/Page column 88
(2009/01/24)
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- In-depth study of tripeptide-based α-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1′ subsite and its implications to structure-based drug design
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Thrombin inhibitors are potentially useful in medicine for their anticoagulant and antithrombotic effects. We synthesized and evaluated diverse heterocycle-activated ketones based on the D-Phe-Pro-Arg, and related thrombin active-site recognition motifs, as candidate inhibitors. The peptide-based α-ketoheterocycles were typically prepared by either an imidate or a Weinreb amide route (Schemes 1 and 2), the latter of which proved to be more general. Test compounds were generally assayed for inhibition of human α-thrombin and bovine trypsin. From a structure-based design standpoint, the heterocycle allows one to explore and adjust interactions within the S1′ subsite of thrombin. The preferred α-ketoheterocycle is a π-rich 2-substituted azole with at least two heteroatoms proximal to the carbon bearing the keto group, and a preferred thrombin inhibitor is 2-ketobenzothiazole 3, with a potent Ki value of 0.2 nM and ca. 15-fold selectivity over trypsin. 2-Ketobenzothiazole 13 exhibited exceedingly potent thrombin inhibition (Ki = 0.000 65 nM; slow tight binding). Several α-ketoheterocycles had thrombin Ki values in the range 0.1-400 nM. The "Arg" unit in the α-ketoheterocycles can be sensitive to stereomutation under mildy basic conditions. For example, 2-ketothiazoles 4 and 59 readily epimerize at pH 7.4, although they are fairly stable stereochemically at pH 3-4; thus, suitable conditions had to be selected for the enzymatic assays. Lead D-Phe-Pro-Arg 2-benzothiazoles 3, 4, and 68 displayed good selectivity for thrombin over other key coagulation enzymes (e.g., factor Xa, plasmin, protein Ca, uPA, tPA, and streptokinase); however, their selectivity for thrombin over trypsin was modest (50 = 30-40 nM). They also proved to be potent anticoagulant/ antithrombotic agents in vivo on intravenous administration, as determined in the canine arteriovenous shunt (ED50 = 0.45-0.65 mg/kg) and the rabbit deep vein thrombosis (ED50 = 0.1-0.4 mg/kg) models. Intravenous administration of 3, and several analogues, to guinea pigs caused hypotension and electrocardiogram abnormalities. Such cardiovascular side effects were also observed with some nonguanidine inhibitors and inhibitors having recognition motifs other than D-Phe-Pro-Arg. 2-Benzothiazolecarboxylates 4 and 68 exhibited significantly diminished cardiovascular side effects, and benzothiazolecarboxylic acid 4 had the best profile with respect to therapeutic index. The X-ray crystal structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S1′ region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate of 4 forms a salt bridge with the side chain of Lys-60F such that it adopts an extended anti conformation. Since 3 has a 10-fold greater affinity for thrombin than does 4, any increase in binding energy resulting from this salt bridge is apparently offset by perturbations across the enzyme (viz. Figure 4). The increased affinity and selectivity of 2-ketobenzothiazole inhibitors, such as 3, may be primarily due to the aromatic stacking interaction with Trp-60D. However, energy contour calculations with the computer program GRID also indicate a favorable interaction between the benzothiazole sulfur atom and a hydrophobic patch on the surface of thrombin.
- Costanzo, Michael J.,Almond Jr., Harold R.,Hecker, Leonard R.,Schott, Mary R.,Yabut, Stephen C.,Zhang, Han-Cheng,Andrade-Gordon, Patricia,Corcoran, Thomas W.,Giardino, Edward C.,Kauffman, Jack A.,Lewis, Joan M.,De Garavilla, Lawrence,Haertlein, Barbara J.,Maryanoff, Bruce E.
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p. 1984 - 2008
(2007/10/03)
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- ACETYLENE DERIVATIVES AS INHIBITORS OF HISTONE DEACETYLASE
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The present invention is directed to certain hydroxamate derivatives that are inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.
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Page/Page column 54
(2010/02/11)
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- Method for the synthesis of compounds of formula 1 and derivatives thereof
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Mono-substituted and di-substituted alpha-amino acids and derivatives thereof, substituted at the alpha positon with one (mono-) or two (di-) substituents (R2 and/or R3) as shown in Formula 1: N(R4R5)C(R2R3)CO(OR1).
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- ARYLGLYCINE DERIVATIVES AND THEIR USE AS GLYCINE TRANSPORT INHIBITORS
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The present invention relates to compounds of Formula (I), and salts solvates and hydrates thereof. The invention further relates to pharmaceutical compositions containing said compounds and methods of treating neurological, neuropsychiatric, and gastrointestinal disorders using said compounds.
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- ARYLGLYCINE DERIVATIVES FOR USE AS GLYCINE TRANSPORT INHIBITORS
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The present invention relates to compounds of Formula (I) and salts solvates and hydrates thereof. The invention further relates to pharmaceutical compositions containing said compounds and methods of treating neurological and neuropsychistric disorders using said compounds.
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- Dipeptide nitriles
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N-terminal substituted dipeptide nitriles as defined are useful as inhibitors of cysteine cathepsins, e.g. cathepsins B, K, L and S, and can be used for the treatment of cysteine cathepsin dependent diseases and conditions, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization). Particular dipeptide nitriles are compounds of formula I, or physiologically-acceptable and -cleavable esters or a salts thereof wherein: the symbols are as defined. In particular it has been found that by appropriate choice of groups R, R2, R3, R4, R5, X1, Y and L, the relative selectivity of the compounds as inhibitors of the various cysteine cathepsin types, e.g. cathepsins B, K, L and S may be altered, e.g. to obtain inhibitors which selectively inhibit a particular cathepsin type or combination of cathepsin types.
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Page column 32-33
(2010/02/05)
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- Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores
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Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg-1, TD50 = 36.4 mg kg-1, PI = 6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.
- Ho, Bin,Michael Crider,Stables, James P
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p. 265 - 286
(2007/10/03)
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- Hydrogen-bonded tapes based on symmetrically substituted diketopiperazines: A robust structural motif for the engineering of molecular solids
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A series of eight symmetrically substituted diketopiperazines (DKPs) derived from 1-amino-1-carboxycycloalkanes (n = 3-7; 3,3,5,5-tetramethylcyclohexane; 4,4-dimethylcyclohexane; 2-indan) were synthesized and their crystal structures determined. In the solid state, all eight compounds form two pairs of hydrogen bonds with two adjacent molecules to form a one-dimensional structure that we refer to as 'tapes'. These molecules represent a range of volumes and shapes that contain a common molecular fragment (DKP ring). We examined this series of compounds with three objectives in mind: (i) to establish the ability of the hydrogen-bonded 'tape' motif to persist through these differences in volume and shape; (ii) to provide a series of structurally related compounds to use to test computational methods of predicting crystal structure from molecular structure; (iii) to search for qualitative correlations between molecular structure and crystal packing. All compounds form tapes and with one exception, all tapes pack with their long axes parallel. When viewed down their long axis, two types of tapes emerge: planar and nonplanar. The type of tape that forms reflects the conformation adapted by the DKP ring-planar or boat. Planar tapes form when the angle (α) between the two planes defined by the cis-amides in the DKP ring is 180°; nonplanar tapes form when α 180°. Five of the eight compounds studied form planar tapes, the remaining three compounds form nonplanar tapes. Despite the variability in volume and shape represented by this series of molecules, the persistence of the tape motif in their crystalline solids suggests that the hydrogen-bonding interactions between parallel alignment of tapes that pack in a manner that permits the interdigitation of substituents on adjacent tapes.
- Palacin, Serge,Chin, Donovan N.,Simanek, Eric E.,MacDonald, John C.,Whitesides, George M.,McBride, Mary T.,Palmore, G. Tayhas R.
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p. 11807 - 11816
(2007/10/03)
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- RENIN INHIBITING COMPOUNDS
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Compounds which are amino acid derivatives and have the formula STR1 in which R 1 is hydrogen or methyl, R 2 is ethyl, propyl or imidazol-4-yl, R 3 is isobutyl, cyclohexylmethyl or benzyl, and A is defined as herein are useful as renin inhibitors.
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