ABSTRACT
An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.
Subject(s)
Asthma/drug therapy , Butyrates/pharmacology , Butyrates/therapeutic use , Indoles/pharmacology , Indoles/therapeutic use , Leukotriene Antagonists/pharmacology , Leukotriene Antagonists/therapeutic use , Receptors, Leukotriene/drug effects , Animals , Biological Availability , Dogs , Guinea Pigs , Humans , Leukotriene Antagonists/pharmacokinetics , RatsABSTRACT
A potent, orally available dual CysLT1 and CysLT2 receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO-4310321, IC50: CysLT1=13nM, CysLT2=25 nM) showed excellent pharmacokinetic profiles (%Frat=100) compared with our previously reported compound 1 (%Frat=1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%Frat⩾40) in rats (HBDs: ⩽2, ClogP: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification.
Subject(s)
Dicarboxylic Acids/administration & dosage , Dicarboxylic Acids/pharmacology , Drug Discovery , Leukotriene Antagonists/administration & dosage , Leukotriene Antagonists/pharmacology , Receptors, Leukotriene/metabolism , Administration, Oral , Animals , Biological Availability , CHO Cells , Caco-2 Cells , Cricetulus , Dicarboxylic Acids/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Leukotriene Antagonists/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
The benzoxazine derivative, (2S)-4-(3-carboxypropyl)-8-{[4-(4-phenylbutoxy)benzoyl]amino}-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (19, ONO-2050297), was identified as the first potent dual CysLT1 and CysLT2 antagonist with IC50 values of 0.017 µM (CysLT1) and 0.00087 µM (CysLT2), respectively.
ABSTRACT
A series of 4-(4-phenoxy)benzoylamino-4-methoxymethyloxymethyl butyric acid hydroxamates, which were derived from l-glutamic acid, were synthesized and evaluated as matrix metalloproteinase inhibitors. Most of the compounds listed in exhibited strong inhibitory activity against MMP-2 and MMP-9, as well as even stronger inhibitory activity against MMP-3, but showed relatively weak inhibition of MMP-1. Structure-activity relationships are discussed.
Subject(s)
Benzamides , Drug Design , Hydroxamic Acids , Matrix Metalloproteinase Inhibitors , Protease Inhibitors , Administration, Oral , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Glutamic Acid/chemistry , Guinea Pigs , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Male , Molecular Conformation , Protease Inhibitors/administration & dosage , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of N-benzoyl 4-aminobutyric acid hydroxamate analogs were synthesized and evaluated as matrix metalloproteinase inhibitors. Synthetic work was focused on the chemical modification of the 4-aminobutyric acid part using easily available starting materials. As such, chemical modification was carried out using commercially available starting materials such as 4-aminobutyric acid, (+)- and (-)-malic acid, and D- and L-glutamic acid derivatives. Among the compounds tested, N-[4-(benzofuran-2-yl)benzoyl] 4-amino-4S-hydroxymethylbutyric acid hydroxamates derived from L-glutamic acid demonstrated more potent inhibitory activity against MMP-2 and MMP-9 compared with the corresponding 2S-hydroxy analogs or 3S-hydroxy analogs, respectively, which were derived from (-)-malic acid. Structure-activity relationship study is presented.
Subject(s)
Benzofurans , Butyrates , Drug Design , Enzyme Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors , Tissue Inhibitor of Metalloproteinases , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzofurans/pharmacology , Butyrates/chemical synthesis , Butyrates/chemistry , Butyrates/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Tissue Inhibitor of Metalloproteinases/chemical synthesis , Tissue Inhibitor of Metalloproteinases/chemistry , Tissue Inhibitor of Metalloproteinases/pharmacologyABSTRACT
Discovery of new chemical leads of inhibitors for TNF-alpha production starting from the chemical modification of 1 is reported. Further biological studies of 1 to disclose the site of its action strongly suggested that 1 inhibits LPS-induced TNF-alpha expression in the liver and spleen of mice. Structure-activity relationships (SARs) are also discussed and full details including the chemistry are reported.
Subject(s)
Indans/chemical synthesis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Female , Indans/administration & dosage , Indans/pharmacology , Inhibitory Concentration 50 , Injections, Intravenous , Lipopolysaccharides/pharmacology , Liver/chemistry , Male , Mice , Mice, Inbred BALB C , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/pharmacology , Spleen/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Design and synthesis of metabolically stabilized inhibitors of TNF-alpha production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18. Structure-activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported.
Subject(s)
Indans/chemical synthesis , Indans/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Chemical and Drug Induced Liver Injury/drug therapy , Drug Stability , Indans/chemistry , Injections, Intravenous , Lipopolysaccharides/pharmacology , Maximum Tolerated Dose , Mice , Molecular Conformation , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Rats , Shock, Septic/chemically induced , Shock, Septic/drug therapy , Stereoisomerism , Structure-Activity Relationship , Survival Rate , Tissue Distribution , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The discovery of 2-acylamino-2-phenylethyl disodium phosphates and as structurally novel inhibitors of TNF-alpha production is reported. Structure-activity relationships (SARs) are also discussed.
Subject(s)
Adjuvants, Immunologic/chemical synthesis , Benzylamines/chemical synthesis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/pharmacology , Animals , Benzylamines/administration & dosage , Benzylamines/pharmacology , Lipopolysaccharides/administration & dosage , Male , Mice , Mice, Inbred BALB C , Phosphates/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Metabolic stabilization of the chemical lead 1, which is a structurally novel inhibitor of TNF-alpha production, was accomplished by introducing a (1S)-methyl group into the optically active backbone. As a result, 2, 3 and 4 were identified as drug candidates and evaluated pharmacologically. The analysis of an active conformer was also carried out.
