RESUMO
To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.
Assuntos
Lactamas/química , Prostaglandinas/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Administração Oral , Animais , Prostaglandinas/síntese química , Prostaglandinas/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Tiazolidinas/química , Fator de Necrose Tumoral alfa/sangueRESUMO
To identify structurally novel CRF1 receptor antagonists, a series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines, imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 receptor antagonists. Compounds 2-27 showed binding affinity (IC(50)=4.2-418 nM) and antagonist activity (EC(50)=4.0-889 nM). Compound 5 was found to show oral efficacy in an Elevated Plus Maze test in rats. Further chemical modification of them led us to discovery of the tricyclic core antagonists pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidines. The discovery process of these compounds is presented, as is the study of the structure-activity relationship.
Assuntos
Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/química , Animais , Humanos , Cinética , Masculino , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
Assuntos
Fármacos Anti-HIV/química , Benzoatos/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Benzoatos/síntese química , Benzoatos/farmacocinética , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Cobaias , Haplorrinos , Humanos , Coelhos , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Compostos de Espiro/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Dicetopiperazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Proteína do Núcleo p24 do HIV/metabolismo , HIV-1/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Receptores CCR5/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , EstereoisomerismoRESUMO
Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.