RESUMO
Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.
RESUMO
A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative 5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist 11b as a lead compound for the development of an antiglaucoma agent.
RESUMO
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.
Assuntos
Asma/tratamento farmacológico , Butiratos/farmacologia , Butiratos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Antagonistas de Leucotrienos/farmacologia , Antagonistas de Leucotrienos/uso terapêutico , Receptores de Leucotrienos/efeitos dos fármacos , Animais , Disponibilidade Biológica , Cães , Cobaias , Humanos , Antagonistas de Leucotrienos/farmacocinética , RatosRESUMO
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.
Assuntos
Ácidos Dicarboxílicos/administração & dosagem , Ácidos Dicarboxílicos/farmacologia , Descoberta de Drogas , Antagonistas de Leucotrienos/administração & dosagem , Antagonistas de Leucotrienos/farmacologia , Receptores de Leucotrienos/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Células CACO-2 , Cricetulus , Ácidos Dicarboxílicos/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Antagonistas de Leucotrienos/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of 4-([2-[alkyl(phenylsulfonyl)amino]phenoxy]methyl)benzoic acids were identified as functional PGE(2) antagonists with selectivity for the EP1 receptor subtype starting from a chemical lead 1, which was found while screening our in-house compound library. Discovery of the optimized analogs 21-23 is presented here and structure-activity relationships (SAR) are also discussed.
Assuntos
Analgésicos/farmacologia , Benzoatos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Sulfonamidas/farmacologia , Analgésicos/síntese química , Animais , Benzoatos/síntese química , Sítios de Ligação , Células CHO , Cricetinae , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
A series of N-(p-alkoxy)benzoyl-5-methoxy-2-methylindole-3-acetic acids and N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid were discovered as new chemical leads for a prostaglandin D2 (PGD2) receptor antagonist. Most of them exhibited PGD2 receptor binding and blocked cyclic adenosine 3',5'-monophosphate (cAMP) formation in vitro. In particular, 2-methylindole-4-acetic acid analog 1 showed markedly increased receptor affinity and cAMP antagonist activity. Chemistry and structure activity relationship (SAR) data are also presented.
Assuntos
Ácidos Indolacéticos/síntese química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Área Sob a Curva , Ligação Competitiva/fisiologia , Células CHO , Cricetinae , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/metabolismo , Meia-Vida , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacocinética , Indometacina/análogos & derivados , Indometacina/química , Indometacina/farmacocinética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-AtividadeRESUMO
A series of Indomethacin analogs were synthesized and biologically evaluated. Among the compounds tested, N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid 2 was discovered as a new chemical lead for a prostaglandin D2 (PGD2) receptor antagonist. Structure-activity relationship data are also presented.
Assuntos
Antagonistas de Prostaglandina/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Camundongos , Antagonistas de Prostaglandina/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.
Assuntos
Halogênios/química , Prostaglandinas F Sintéticas/síntese química , Prostaglandinas F Sintéticas/farmacologia , Animais , Células CHO , Cricetinae , Cristalografia por Raios X , AMP Cíclico/metabolismo , Conformação Molecular , Estrutura Molecular , Prostaglandinas F Sintéticas/química , Receptores de Prostaglandina E/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the alpha chain of PGE1 was investigated. Among the compounds tested, 3,7-dithiaPGE1 4a exhibited good EP4-receptor selectivity and agonist activity. Further modification of the omega chain of 3,7-dithiaPGE1 was performed to improve EP4-receptor selectivity and agonist activity. Of the compounds produced, 16-phenyl-omega-tetranor-3,7-dithiaPGE1 4p possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety.
Assuntos
Alprostadil/farmacologia , Receptores de Prostaglandina E/agonistas , Alprostadil/análogos & derivados , Alprostadil/química , Animais , Células CHO , Cálcio/análise , Cricetinae , AMP Cíclico/metabolismo , Desenho de Fármacos , Ligação Proteica , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-Atividade , SulfetosRESUMO
Further chemical modification of 1a and 2 was undertaken to identify a more chemically stable selective EP2-receptor agonist for development as a clinical candidate. 9beta-chloro PG analogues 4a-e and 5a, c-e were found to be potent and selective EP2-receptor agonists. Among them, the compound 4aLy, which is a chemically stabilized lysine salt of 4a, exhibited an excellent profile both in biological activities and physicochemical properties. The agonist 4aLy was found to suppress uterine motility in anesthetized pregnant rats, while PGE2 stimulated uterine motility. Structure-activity relationships (SARs) are discussed.