Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 66(18): 13135-13147, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37724542

RESUMO

A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable in vitro profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight. Subsequent studies in MGAT2 knockout mice with the lead candidate 12 (BMS-986172) showed on-target- and mechanism-based pharmacology. Moreover, its favorable pharmacokinetic (PK) profile and the lack of species variability in the glucuronidation potential resulted in a greater confidence level in the projection of a low dose for achieving targeted efficacious exposures in humans. Consistent with these projections, PK data from a phase 1 trial confirmed that targeted efficacious exposures could be achieved at a low dose in humans, which supported compound 12 as our second and potentially superior development candidate for the treatment of various metabolic disorders.


Assuntos
Doenças Metabólicas , Piridonas , Animais , Humanos , Camundongos , Peso Corporal , Doenças Metabólicas/tratamento farmacológico , Piridonas/química , Piridonas/farmacologia , N-Acetilglucosaminiltransferases/antagonistas & inibidores
2.
J Med Chem ; 64(19): 14773-14792, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34613725

RESUMO

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Doenças Metabólicas/tratamento farmacológico , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Relação Estrutura-Atividade
3.
J Med Chem ; 56(23): 9586-600, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24182233

RESUMO

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.


Assuntos
Piridazinas/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Triazóis/farmacocinética , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Meia-Vida , Ligação Proteica , Piridazinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/química
4.
Bioorg Med Chem Lett ; 23(13): 3914-9, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23683593

RESUMO

The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.


Assuntos
Isoquinolinas/farmacologia , Pirazinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Modelos Moleculares , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Ratos , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 23(1): 330-5, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23177783
6.
Bioorg Med Chem Lett ; 21(22): 6856-60, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21962575

RESUMO

Obesity remains a significant public health issue leading to Type II diabetes and cardiovascular disease. CB1 antagonists have been shown to suppress appetite and reduce body weight in animal models as well as in humans. Evaluation of pre-clinical CB1 antagonists to establish relationships between in vitro affinity and in vivo efficacy parameters are enhanced by ex vivo receptor occupancy data. Synthesis and biological evaluation of a novel and highly selective radiolabeled CB1 antagonist is described. The radioligand was used to conduct ex vivo receptor occupancy studies.


Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Ensaio Radioligante/métodos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Humanos , Obesidade/tratamento farmacológico , Radiografia , Ratos
7.
Bioorg Med Chem Lett ; 20(3): 1128-33, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20022752

RESUMO

Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.


Assuntos
Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Quinazolinonas/química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Humanos , Masculino , Obesidade/metabolismo , Ligação Proteica/fisiologia , Quinazolinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/metabolismo
8.
J Biol Chem ; 283(44): 29802-11, 2008 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-18768481

RESUMO

Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of the four intestinal membrane bound acyltransferases implicated in dietary fat absorption. Recently, it was found that, in addition to acylating diacylglycerol (DAG), DGAT1 also possesses robust enzymatic activity for acylating monoacylglycerol (MAG) (Yen, C. L., Monetti, M., Burri, B. J., and Farese, R. V., Jr. (2005) J. Lipid Res. 46, 1502-1511). In the current paper, we have conducted a detailed characterization of this reaction in test tube, intact cell culture, and animal models. Enzymatically, we found that triacylglycerol (TAG) synthesis from MAG by DGAT1 does not behave according to classic Michaelis-Menten kinetics. At low concentrations of 2-MAG (<50 microm), the major acylation product by DGAT1 was TAG; however, increased concentrations of 2-MAG (50-200 microm) resulted in decreased TAG formation. This unique product/substrate relationship is similar to MGAT3 but distinct from DGAT2 and MGAT2. We have also found that XP620 is an inhibitor that selectively inhibits the acylation of MAG by DGAT1 (IC(50) of human DGAT1: 16.6+/-4.0 nM (MAG as substrate) and 1499+/-318 nM (DAG as substrate); IC(50) values of human DGAT2, MGAT2, and MGAT3 are >30,000 nM). Using this pharmacological tool, we have shown that approximately 76 and approximately 89% of the in vitro TAG synthesis initiated from MAG is mediated by DGAT1 in Caco-2 cell and rat intestinal mucosal membranes, respectively. When applied to intact cultured cells, XP620 substantially decreased but did not abolish apoB secretion in differentiated Caco-2 cells. It also decreased TAG and DAG syntheses in primary enterocytes. Last, when delivered orally to rats, XP620 decreased absorption of orally administered lipids by approximately 50%. Based on these data, we conclude that the acylation of acylglycerols by DGAT1 is important for dietary fat absorption in the intestine.


Assuntos
Diacilglicerol O-Aciltransferase/biossíntese , Gorduras/metabolismo , Regulação da Expressão Gênica , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Administração Oral , Animais , Células CACO-2 , Diacilglicerol O-Aciltransferase/fisiologia , Gorduras na Dieta , Enterócitos/metabolismo , Compostos Heterocíclicos com 1 Anel , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
9.
J Med Chem ; 50(6): 1365-79, 2007 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-17315987

RESUMO

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.


Assuntos
Fármacos Antiobesidade/síntese química , Indóis/síntese química , Pirazinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Condicionamento Operante , Comportamento Alimentar/efeitos dos fármacos , Humanos , Indóis/química , Indóis/farmacologia , Isoindóis , Masculino , Camundongos , Necrose , Células Parietais Gástricas/efeitos dos fármacos , Células Parietais Gástricas/patologia , Pirazinas/química , Pirazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Aumento de Peso/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...