RESUMO
Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Macrocíclicos/farmacologia , Receptor de Pregnano X/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Receptor de Pregnano X/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
AIM: High clearance is a commonly encountered issue in drug discovery. Here we present a centralized metabolic soft spot identification assay with adequate capacity and turnaround time to support the metabolic optimization needs of an entire discovery organization. METHODOLOGY: An integrated quan/qual approach utilizing both an orthogonal sample-pooling methodology and software-assisted structure elucidation was developed to enable the assay. Major metabolic soft spots in liver microsomes (rodent and human) were generated in a batch mode, along with kinetics of parent disappearance and metabolite formation, typically within 1 week of incubation. RESULTS & CONCLUSION: A centralized metabolic soft spot identification assay has been developed and has successfully impacted discovery project teams in mitigating instability and establishing potential structure-metabolism relationships.
Assuntos
Cromatografia Líquida/normas , Descoberta de Drogas/métodos , Metabolômica/métodos , Microssomos Hepáticos/metabolismo , Software , Espectrometria de Massas em Tandem/normas , Animais , Bioensaio , Humanos , Cinética , Camundongos , RatosRESUMO
(E)-3-(Benzenesulfonyl)-2-(methylsulfanyl)pyrido[1,2-a]pyrimidin-4-ylidenamine (7) was found to be a potent and selective 5-HT(6) antagonist. A one-step synthesis of this compound is described.