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1.
Bioorg Med Chem Lett ; 30(21): 127574, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32980512

RESUMO

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Descoberta de Drogas , Hipertensão/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Anti-Hipertensivos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 29(24): 126104, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30389294

RESUMO

Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.


Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo
4.
J Med Chem ; 51(3): 589-602, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18201067

RESUMO

A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.


Assuntos
Amidas/síntese química , Inibidores da Dipeptidil Peptidase IV , Piperazinas/síntese química , Pirazinas/síntese química , Triazóis/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Cristalografia por Raios X , Dipeptidil Peptidase 4/química , Cães , Teste de Tolerância a Glucose , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacocinética , Piperazinas/farmacologia , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia
5.
ACS Med Chem Lett ; 7(1): 111-6, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819676

RESUMO

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

6.
Bioorg Med Chem Lett ; 14(18): 4763-6, 2004 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-15324904

RESUMO

Incorporation of a fluorophenyl beta-amino amide moiety into piperazine screening lead 2 has resulted in the discovery of a structurally novel series of potent and selective DP-IV inhibitors. Simplification of the molecule and incorporation of multiple fluorine atoms on the phenyl ring has provided low molecular weight analogs such as compound 32, which is a 19nM DP-IV inhibitor with >4000-fold selectivity over QPP.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Piperazinas/farmacologia , Inibidores de Proteases/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
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