RESUMO
Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and has therapeutic potential for T cell-mediated diseases such as transplant rejection and rheumatoid arthritis. PKCθ inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the 2,4-diamino-5-cyanopyrimidine derivative 2 was a potent PKCθ inhibitor; however, it exhibited CYP3A4 time-dependent inhibition (TDI). Here, we report the structural modification of compound 2 into 34 focusing on mitigating CYP3A4 TDI. Compound 34 exhibited potent in vitro activity with mitigated CYP3A4 TDI and efficacy in vivo transplant model.
Assuntos
Diaminas/farmacologia , Proteína Quinase C-theta/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Diaminas/síntese química , Diaminas/farmacocinética , Descoberta de Drogas , Interações Medicamentosas , Feminino , Rejeição de Enxerto/prevenção & controle , Haplorrinos , Humanos , Células Jurkat , Microssomos Hepáticos/metabolismo , Midazolam/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos Endogâmicos ACI , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and is an attractive target for the treatment of T cell-mediated diseases such as transplant rejection and autoimmune disease. To identify PKCθ inhibitors, we focused on the 2,6-diamino-3-carbamoyl-5-cyanopyrazine derivative 2, which exhibited moderate PKCθ inhibitory activity. Optimization of 2 identified the 2,4-diamino-5-cyanopyrimidine derivative 16c, which exhibited potent PKCθ inhibitory activity and showed good selectivity against other PKC isozymes. Compound 16c prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração/métodos , Proteína Quinase C-theta/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Animais , Feminino , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração/efeitos adversos , Humanos , Simulação de Acoplamento Molecular , Proteína Quinase C-theta/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ratos Sprague-Dawley , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodosRESUMO
[Structure: see text] The total synthesis of pseudo 2-epibotcinolide (1b) through several featured synthetic approaches has been attained. First, the chiral linear precursors of the nine-membered ring compound is stereoselectively constructed by the asymmetric aldol reaction for producing beta-hydroxy ester units. Second, the key cyclization reaction to form the nine-membered lactone moiety is efficiently achieved by the extremely facile and powerful mixed-anhydride method promoted by 2-methyl-6-nitrobenzoic anhydride (MNBA) with basic promoters.
Assuntos
Decanoatos/síntese química , Lactonas/síntese química , Pironas/síntese química , Botrytis/metabolismo , Ciclização , Decanoatos/metabolismo , Lactonas/metabolismo , Estrutura Molecular , Pironas/metabolismoRESUMO
Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.