RESUMO
A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.
Assuntos
Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Dipeptidil Peptidase 4/metabolismo , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/metabolismo , Receptores CCR5/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
A novel molecular scaffold has been synthesized, and its synthesis and incorporation into new analogues of biologically active molecules will be discussed. A comparison of the inhibitory activity of these compounds to the known type-2 diabetes compound (sitagliptin) against dipeptidyl peptidase-4 (DPP-4) will be shown.
RESUMO
Bicycle ring closure on a mixture of (4aS,8aR)- and (4aR,8aS)-ethyl 2-oxodecahydro-1,6-naphthyridine-6-carboxylate, followed by conversion of the separated cis and trans isomers to the corresponding thioamide derivatives, gave (4aSR,8aRS)-ethyl 2-sulfanylidenedecahydro-1,6-naphthyridine-6-carboxylate, C11H18N2O2S. Structural analysis of this thioamide revealed a structure with two crystallographically independent conformers per asymmetric unit (Z' = 2). The reciprocal bicycle ring closure on (3aRS,7aRS)-ethyl 2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-carboxylate, C10H16N2O3, was also accomplished in good overall yield. Here the five-membered ring is disordered over two positions, so that both enantiomers are represented in the asymmetric unit. The compounds act as key intermediates towards the synthesis of potential new polycyclic medicinal chemical structures.