RESUMO
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Assuntos
Descoberta de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Isoquinolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Relação Dose-Resposta a Droga , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Isoquinolinas/administração & dosagem , Isoquinolinas/química , Lactamas , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
A novel method for the kinetic resolution of unsymmetrical acyclic allylic carbonates and the concurrent synthesis of enantioenriched secondary amines using a commercially available chiral catalyst is disclosed.
Assuntos
Compostos Alílicos/química , Aminas/síntese química , Carbonatos/química , Ródio/química , Aminas/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.