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1.
ACS Med Chem Lett ; 13(4): 734-741, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35450359

RESUMO

Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and ∼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed. The hypothesis for GSH-adduct formation was driven by the electron-rich nature of the tricyclic core. Herein, we describe our efforts to reduce the electron-rich nature of the core. Ultimately, a strategy focused on core modifications to block metabolic hot spots coupled with substitution pattern changes (C8 N → C linked) led to the identification of new tricyclic analogues with minimal GSH-adduct formation across species while maintaining an overall balanced profile.

2.
J Med Chem ; 65(7): 5575-5592, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35349275

RESUMO

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.


Assuntos
Infarto do Miocárdio , Trombose , Animais , Humanos , Lactonas , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária , Ratos , Receptor PAR-1 , Receptores Ativados por Proteinase , Trombose/induzido quimicamente , Trombose/tratamento farmacológico
3.
PLoS One ; 14(2): e0211568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30811418

RESUMO

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Animais , Metabolismo Energético , Ativação Enzimática/efeitos dos fármacos , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Homeostase , Camundongos Endogâmicos C57BL , Oxirredução , Condicionamento Físico Animal
4.
ACS Med Chem Lett ; 9(1): 39-44, 2018 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-29348809

RESUMO

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and weight loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. We describe the optimization of ß1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compounds proved essential in improving ß2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration.

5.
Science ; 357(6350): 507-511, 2017 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-28705990

RESUMO

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cardiomegalia/induzido quimicamente , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Imidazóis/farmacologia , Piridinas/farmacologia , Animais , Benzimidazóis , Glicemia/efeitos dos fármacos , Jejum , Glicogênio/metabolismo , Hipoglicemia/induzido quimicamente , Imidazóis/efeitos adversos , Imidazóis/química , Insulina/farmacologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Piridinas/efeitos adversos , Piridinas/química
6.
Bioorg Med Chem Lett ; 26(11): 2622-6, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27106708

RESUMO

Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Descoberta de Drogas , Pirrolidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Cães , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 25(24): 5767-71, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26546218

RESUMO

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.


Assuntos
Amidas/química , Inibidores da Dipeptidil Peptidase IV/química , Compostos Heterocíclicos com 2 Anéis/química , Piranos/química , Sulfonamidas/química , Animais , Sítios de Ligação , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Meia-Vida , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Piranos/síntese química , Piranos/farmacocinética , Ratos , Relação Estrutura-Atividade
8.
ACS Med Chem Lett ; 6(5): 553-7, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005532

RESUMO

Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.

9.
J Med Chem ; 57(8): 3205-12, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24660890

RESUMO

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Hipoglicemiantes/farmacologia , Piranos/farmacologia , Animais , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/toxicidade , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/toxicidade , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/toxicidade , Piranos/síntese química , Piranos/farmacocinética , Piranos/toxicidade , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 24(4): 1111-5, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24461292

RESUMO

Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were prepared and evaluated for activity against thrombin, clotting factors VIIa, IXa, Xa, and XIIa, and trypsin. The thiomorpholine analog 6 was the most active, essentially matching the thrombin inhibitory activity of 1 with slightly improved selectivity over trypsin.


Assuntos
Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Trombina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Trombina/metabolismo
11.
Bioorg Med Chem Lett ; 23(19): 5361-6, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23972441

RESUMO

A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.


Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Piranos/síntese química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Cães , Ativação Enzimática/efeitos dos fármacos , Teste de Tolerância a Glucose , Haplorrinos , Humanos , Concentração Inibidora 50 , Piranos/química , Piranos/farmacologia , Ratos , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 18(13): 3706-10, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18524582

RESUMO

Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors.


Assuntos
Dipeptidil Peptidase 4/química , Sítios de Ligação , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Inibidores da Dipeptidil Peptidase IV , Desenho de Fármacos , Flúor/química , Glicina/química , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Modelos Teóricos , Conformação Molecular , Software , beta-Alanina/química
16.
Eur J Med Chem ; 43(6): 1123-51, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17981367

RESUMO

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.


Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Espectrometria de Massas por Ionização por Electrospray
17.
Bioorg Med Chem Lett ; 17(13): 3558-61, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17475489

RESUMO

Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed.


Assuntos
Coccidiose/tratamento farmacológico , Coccidiostáticos/farmacologia , Imidazóis/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Química Farmacêutica/métodos , Coccidiostáticos/química , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Desenho de Fármacos , Eimeria tenella , Modelos Químicos , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 17(14): 3877-9, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17502141

RESUMO

Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Desenho de Fármacos , Modelos Moleculares , Inibidores de Proteases/química , Pirimidinas/química , Relação Quantitativa Estrutura-Atividade
19.
Eur J Med Chem ; 42(11-12): 1334-57, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17433505

RESUMO

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.


Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Eimeria/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Disponibilidade Biológica , Coccidiostáticos/química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Eimeria/fisiologia , Imidazóis/química , Concentração Inibidora 50 , Piridinas/química
20.
Bioorg Med Chem Lett ; 17(12): 3384-7, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17433672

RESUMO

Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.


Assuntos
Inibidores de Adenosina Desaminase , Cicloexilaminas/química , Inibidores da Dipeptidil Peptidase IV , Glicoproteínas/antagonistas & inibidores , Inibidores da Protease de HIV/farmacologia , Pirazinas/farmacologia , Triazóis/farmacologia , Administração Oral , Sítios de Ligação , Cristalografia por Raios X , Dipeptidil Peptidase 4 , Desenho de Fármacos , Inibidores da Protease de HIV/síntese química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Pirazinas/química , Fosfato de Sitagliptina , Triazóis/química
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