RESUMO
Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5. Therefore, the lead optimization program mainly focused on the improvement in potency and oral bioavailability. Data of newly synthesized analogs were collected from in vitro pharmacological, physicochemical, in vitro ADME, and in vivo pharmacokinetic studies in the rat and the dog. The data were then analyzed using a traffic light selection tool as a visualization device in order to evaluate and prioritize candidates displaying a balanced overall profile. This data-driven process and the excellent results of the PK study in the rat (F = 44%) and the dog (F = 55%) facilitated the identification of 28 as a potent (IC50 = 6 nM), selective, and orally available CRTh2 antagonist.
Assuntos
Indóis/farmacologia , Indóis/farmacocinética , Naftalenos/farmacologia , Naftalenos/farmacocinética , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Indóis/química , Indóis/metabolismo , Masculino , Naftalenos/química , Naftalenos/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
(E)-2-(3-(3-((3-Bromophenyl)amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl)acetic acid (1) was discovered in a HTS campaign for CRTh2 receptor antagonists. An SAR around this hit could be established and representatives with interesting activity profiles were obtained. Ring closing tactics to convert this hit series into a novel 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole based CRTh2 receptor antagonist series is presented.
Assuntos
Acrilamidas/química , Acrilamidas/farmacologia , Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Humanos , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
Hit-to-lead evolution of 2-(2-((2-(4-chlorophenoxy)ethyl)thio)-1H-benzo[d]imidazol-1-yl)acetic acid (1), discovered in a high-throughput screening campaign as a novel chemotype of CRTh2 receptor antagonist, is presented. SAR development as well as in vitro and in vivo DMPK properties of selected representatives of substituted 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids are discussed.
