RESUMEN
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.
Asunto(s)
Asma/tratamiento farmacológico , Butiratos/farmacología , Butiratos/uso terapéutico , Indoles/farmacología , Indoles/uso terapéutico , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Receptores de Leucotrienos/efectos de los fármacos , Animales , Disponibilidad Biológica , Perros , Cobayas , Humanos , Antagonistas de Leucotrieno/farmacocinética , RatasRESUMEN
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.
Asunto(s)
Ácidos Dicarboxílicos/administración & dosificación , Ácidos Dicarboxílicos/farmacología , Descubrimiento de Drogas , Antagonistas de Leucotrieno/administración & dosificación , Antagonistas de Leucotrieno/farmacología , Receptores de Leucotrienos/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Células CHO , Células CACO-2 , Cricetulus , Ácidos Dicarboxílicos/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Antagonistas de Leucotrieno/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
RESUMEN
4-{[2-[(2-Furylsulfonyl)(isobutyl)amino]-5-(trifluoromethyl)phenoxy]methyl}benzoic acid analogs 2a and b and a series of the acid analogs, in which the carboxylic acid residue of 2b was replaced with various kinds of carboxylic acid bioisosteres, were synthesized and evaluated as EP1 receptor antagonists. Compound 2b and its monocyclic acid analogs, in which the carboxylic acid residue of 2b was replaced with monocyclic acid bioisosteres, were found to show potent EP1 receptor antagonist activity. Optimization of the linker Y between the phenyl moiety and the carboxylic acid residue of 2b was also carried out (Table 5). Compounds 2b and 16 and 17 possessing conformationally restricted linker Y were found to show the most optimized potency among the tested compounds. Cytochrome P450 inhibition of optimized compounds was also investigated. Details of the structure-activity relationship study are presented.
Asunto(s)
Ácidos Carboxílicos/química , Receptores de Prostaglandina E/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Células CHO , Cricetinae , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Subtipo EP1 de Receptores de Prostaglandina E , Espectrofotometría InfrarrojaRESUMEN
A series of 4-[(2-{isobutyl[(5-methyl-2-furyl)sulfonyl]amino}phenoxy)methyl]benzoic acids and 4-({2-[isobutyl(1,3-thiazol-2-ylsulfonyl)amino]phenoxy}methyl)benzoic acids were synthesized and evaluated for their EP receptor affinities and EP1 receptor antagonist activities. Further structural optimization was carried out to reduce inhibitory activity against hepatic cytochrome P450 isozymes, which could represent a harmful potential drug interaction. Selected compounds were also evaluated for their binding affinities to hTP, hDP, mFP, and hIP, and for their hEP1 receptor antagonist activities. The results of structure-activity relationship studies are also presented.
Asunto(s)
Receptores de Prostaglandina E/antagonistas & inhibidores , Sulfonamidas/farmacología , Benzoatos/química , Benzoatos/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Humanos , Hígado/enzimología , Unión Proteica , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
4-({2-[Isobutyl(phenylsulfonyl)amino]-5-(trifluoromethyl)phenoxy}methyl)benzoic acid (1) is a functional PGE2 antagonist selective for EP1 receptor subtype. Analogs of 1, in which the phenyl-sulfonyl moiety has been replaced with more hydrophilic heteroarylsulfonyl moieties, exhibited more optimized antagonist activity, while some of them showed in vivo antagonist activity. Structure-activity relationship (SAR) studies are also presented.