RESUMO
Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy. We report the synthesis of a novel, allosteric, macrocyclic MEK1/2 inhibitor that potently inhibits ERK1/2 activity in cultured cells and tissues of mice after systemic administration. Mice with dilated cardiomyopathy caused by a lamin A/C gene mutation have abnormally increased cardiac ERK1/2 activity. In these mice, this novel MEK1/2 inhibitor is well tolerated, improves left ventricular systolic function, decreases left ventricular fibrosis, has beneficial effects on skeletal muscle structure and pathology and prolongs survival. The novel MEK1/2 inhibitor described herein may therefore find clinical utility in the treatment of this rare cardiomyopathy, other types of cardiomyopathy and cancers in humans.
Assuntos
Cardiomiopatia Dilatada/tratamento farmacológico , Modelos Animais de Doenças , Lamina Tipo A/genética , Compostos Macrocíclicos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Cardiomiopatia Dilatada/genética , Relação Dose-Resposta a Droga , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Camundongos , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
We report the synthesis of 2-substituted 7-azabicyclo[2.2.1]heptane glutamic acid analogue 27 from L-serine. Hemiaminal intermediate 2 can be converted to the 2S,3S,5S-trisubstituted pyrrolidine 3 by a tandem Wittig/Michael reaction or to the 2S,3S,5R-trisubstituted pyrrolidine 4 via an iodosulfonamidation reaction. The key transannular alkylation step to form the [2.2.1] ring system involves a beta-elimination of a silyl ether followed by cyclization to afford tert-butyl 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]-2-heptene-1-carboxylate (20). Selective functionalization at C-2 was accomplished by the direct reduction with SmI(2) of 2-keto-3-silyl ether 23 to the C-2 ketone 24, which was converted to alpha,beta-unsaturated ester 25. Stereospecific reduction of the double bond from the exo face leads to a single protected glutamate analogue, tert-butyl (1S,2R,4R)-7-benzyloxycarbonyl-2-(methoxycarbonylmethyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate (27).
RESUMO
The stereospecific synthesis of the functionalized carbapenam core 16 from the serine-derived trisubstituted pyrrolidine 9 is reported. The synthetic strategy relies on synthesizing an appropriately functionalized pyrrolidine, followed by an intramolecular azetidone formation utilizing a modified Mukiyama reagent. The efficient one-pot conversion of the benzenesulfonamide-protected pyrrolidine 9 to the Cbz-protected pyrrolidine 10 is also reported.