RESUMO
Upregulation of the fibroblast growth factor receptor (FGFR) signaling pathway has been implicated in multiple cancer types, including cholangiocarcinoma and bladder cancer. Consequently, small molecule inhibition of FGFR has emerged as a promising therapy for patients suffering from these diseases. First-generation pan-FGFR inhibitors, while highly effective, suffer from several drawbacks. These include treatment-related hyperphosphatemia and significant loss of potency for the mutant kinases. Herein, we present the discovery and optimization of novel FGFR2/3 inhibitors that largely maintain potency for the common gatekeeper mutants and have excellent selectivity over FGFR1. A combination of meticulous structure-activity relationship (SAR) analysis, structure-based drug design, and medicinal chemistry rationale ultimately led to compound 29, a potent and selective FGFR2/3 inhibitor with excellent in vitro absorption, distribution, metabolism, excretion (ADME), and pharmacokinetics in rat. A pharmacodynamic study of a closely related compound established that maximum inhibition of downstream ERK phosphorylation could be achieved with no significant effect on serum phosphate levels relative to vehicle.
Assuntos
Neoplasias , Inibidores de Proteínas Quinases , Receptores de Fatores de Crescimento de Fibroblastos , Animais , Ratos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Transdução de Sinais , Relação Estrutura-Atividade , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/química , Receptores de Fatores de Crescimento de Fibroblastos/efeitos dos fármacosRESUMO
Presented here is a full account on the development of a strategy culminating in the first total synthesis of the architecturally complex daphniphyllum alkaloid, (-)-calyciphylline N. Highlights of the approach include a highly diastereoselective, intramolecular Diels-Alder reaction of a silicon-tethered acrylate; an efficient Stille carbonylation of a sterically encumbered vinyl triflate; a one-pot Nazarov cyclization/proto-desilylation sequence; and the chemoselective hydrogenation of a fully substituted diene ester.
Assuntos
Alcaloides/síntese química , Compostos Policíclicos/síntese química , Alcaloides/química , Ácidos Carboxílicos/química , Técnicas de Química Sintética , Ciclopentanos/química , Compostos de Epóxi/química , Ésteres , Hidrogenação , Compostos Policíclicos/química , EstereoisomerismoRESUMO
The total synthesis of the architecturally complex Daphniphyllum alkaloid (-)-calyciphylline N has been achieved. Highlights of the synthesis include a Et2AlCl-promoted, highly stereoselective, susbtrate-controlled intramolecular Diels-Alder reaction, a transannular enolate alkylation, an effective Stille carbonylation/Nazarov cyclization sequence, and a high-risk diastereoselective hydrogenation of a fully substituted conjugated diene ester.
