RESUMO
Optimisation of a series of biaryl sulphonamides resulted in the identification of compound 14 [corrected] which demonstrated dose-dependent and strain-specific inhibition of monocyte recruitment in a thioglycollate-induced peritonitis model of inflammation. [Formula: see text]. [corrected].
Assuntos
Azóis/química , Receptores CCR2/antagonistas & inibidores , Sulfonamidas/química , Administração Oral , Animais , Azóis/síntese química , Azóis/farmacocinética , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Meia-Vida , Ligação Proteica , Ratos , Receptores CCR2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRASG12C inhibitors. To date, KRASG12C inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding. We report on the discovery of the in vivo active KRASG12C inhibitor BI-0474 using a different approach, in which small molecules that bind reversibly to the switch II pocket were identified and then optimized for non-covalent binding using structure-based design. Finally, the Michael acceptor containing warhead was attached. Our approach offers not only an alternative approach to discovering KRASG12C inhibitors but also provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants.
Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Genes ras , Mutação , Neoplasias/genética , CisteínaRESUMO
The SAR around a V1b antagonist HTS hit 3 was explored to produce a series of thiazole sulfonamides as a lead series with selectivity over the related V1 and oxytocin receptors.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Sulfonamidas/química , Animais , Ensaios de Triagem em Larga Escala , Ratos , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK(a), yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.
Assuntos
Receptores CCR2/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Estrutura Molecular , Receptores CCR1/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.