RESUMO
The Hedgehog (Hh-) signaling pathway is a key developmental pathway which controls patterning, growth and cell migration in most tissues, but evidence has accumulated showing that many human tumors aberrantly reactivate this pathway. Smoothened antagonists offer opportunities for the treatment of malignancies dependent on the Hh pathway, and the most advanced clinical candidates are demonstrating encourage initial results. A novel series of [6,5]-bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione smoothened antagonists has been identified, and the series has been extensively explored to ascertain the key detriments for activity, demonstrating that the trans-2-phenylcyclopropyl and hydantoin ring systems are critical for potency, while a variety of urea substituents can be tolerated. The combination of these optimal groups gives smoothened antagonists with activity in the low nanomolar range.
Assuntos
Antineoplásicos/química , Proteínas Hedgehog/antagonistas & inibidores , Imidazóis/química , Pirazinas/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Hedgehog/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.
Assuntos
Antineoplásicos/química , Proteínas Hedgehog/antagonistas & inibidores , Imidazóis/química , Pirazinas/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Cães , Proteínas Hedgehog/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of hepatitis C virus (HCV) NS3/4A protease inhibitors bearing a P2-P4 macrocycle and a P1-P1' alpha-ketoamide serine trap is reported. The NS3 protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. The optimization of both the macrocycle and the warhead portions led to the discovery of compounds 8b and 8 g with a good activity both in the enzyme as well as in the cell based (replicon) assays with favorable PK profile in a preclinical species.