RESUMO
This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
Assuntos
Benzoatos/síntese química , Benzoatos/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Benzoatos/química , Células CHO , Cricetinae , Cricetulus , Inflamação/induzido quimicamente , Inflamação/complicações , Dor/tratamento farmacológico , Dor/etiologia , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.
Assuntos
Benzoatos/síntese química , Benzoatos/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Área Sob a Curva , Encéfalo/metabolismo , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Indicadores e Reagentes , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
Assuntos
Alprostadil/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Relação Dose-Resposta a Droga , Adjuvante de Freund , Meia-Vida , Inflamação/induzido quimicamente , Inflamação/complicações , Dor/etiologia , RatosRESUMO
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
Assuntos
Analgésicos/farmacologia , Benzoatos/farmacologia , Pirróis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Benzoatos/síntese química , Disponibilidade Biológica , Cicloexanos/química , Ciclopentanos/química , Inflamação/tratamento farmacológico , Inflamação/patologia , Ligantes , Dor/tratamento farmacológico , Dor/patologia , Pirróis/química , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.