RESUMO
The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.
Assuntos
Antivirais/farmacologia , Peptídeos Cíclicos/farmacologia , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/metabolismo , Antivirais/farmacocinética , Células CHO , Cricetulus , Descoberta de Drogas , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacocinética , Ratos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/metabolismo , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
Assuntos
Antivirais/uso terapêutico , Descoberta de Drogas , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/química , Sulfonamidas/químicaRESUMO
Nine new polyprenylated acylphloroglucinol derivatives, hypercohins B-J (1-9), and nine known analogues were isolated from the aerial parts of Hypericum cohaerens. The structures of 1-9 were elucidated based on spectroscopic analysis, and the absolute configuration of 1 was confirmed by X-ray crystallographic analysis. The inhibitory activities of these isolates on acetylcholinesterase and five human tumor cell lines were tested, and hypercohins B-D (1-3) exhibited moderate inhibitory activity (IC50 5.8-17.9 µM) against the tested tumor cell lines.