Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
ACS Med Chem Lett ; 9(7): 673-678, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034599

RESUMO

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.

2.
Medchemcomm ; 8(11): 2093-2099, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108726

RESUMO

Myeloperoxidase, a mammalian peroxidase involved in the immune system as an anti-microbial first responder, can produce hypochlorous acid in response to invading pathogens. Myeloperoxidase has been implicated in several chronic pathological diseases due to the chronic production of hypochlorous acid, as well as other reactive radical species. A high throughput screen and triaging protocol was developed to identify a reversible inhibitor of myeloperoxidase toward the potential treatment of chronic diseases such as atherosclerosis. The identification and characterization of a reversible myeloperoxidase inhibitor, 7-(benzyloxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine is described.

3.
ACS Med Chem Lett ; 7(12): 1207-1212, 2016 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-27994765

RESUMO

Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRß activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.

4.
Cell Metab ; 24(2): 223-33, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27508871

RESUMO

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRß-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.


Assuntos
Movimento Celular , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Metabolismo dos Lipídeos , Lipoproteínas/metabolismo , Receptores X do Fígado/agonistas , Neutrófilos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo/metabolismo , Adolescente , Adulto , Animais , Movimento Celular/efeitos dos fármacos , Colesterol/sangue , Colesterol/metabolismo , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Imidazóis/uso terapêutico , Contagem de Leucócitos , Lipoproteínas/sangue , Macaca fascicularis , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Sistema Fagocitário Mononuclear/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Triglicerídeos/sangue , Adulto Jovem
5.
Bioorg Med Chem Lett ; 26(14): 3278-3281, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27256912

RESUMO

Hydroxyl 1,2-diphenylethanamine analogs were identified as potent inhibitors of cholesterol ester transfer protein (CETP), a therapeutic target to raise HDL cholesterol. In an effort to improve the pharmaceutical properties in the previously disclosed DiPhenylPyridineEthanamine (DPPE) series, polar groups were introduced to the N-linked quaternary center. Optimization of analogues for potency, in vitro liability profile and efficacy led to identification of lead compound 16 which demonstrated robust pharmacodynamic effects in human CETP/apo-B100 dual transgenic mice.


Assuntos
Aminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Descoberta de Drogas , Aminas/síntese química , Aminas/química , Animais , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Relação Estrutura-Atividade
6.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26524347

RESUMO

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Benzamidas/farmacocinética , Benzilaminas/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , HDL-Colesterol/sangue , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inibidores , Cães , Descoberta de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
7.
J Pharmacol Exp Ther ; 352(2): 305-14, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25467132

RESUMO

Liver X Receptors (LXRs) α and ß are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacology of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXRß selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC50 = 610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, respectively, with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are critical for RCT, were comparable. Increased liver triglyceride was observed after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS-779788, a partial LXRß selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRα activity.


Assuntos
Anticolesterolemiantes/farmacologia , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Receptores Nucleares Órfãos/agonistas , Sulfonas/farmacologia , Transportadores de Cassetes de Ligação de ATP/sangue , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/sangue , Relação Dose-Resposta a Droga , Agonismo Parcial de Drogas , Imidazóis/administração & dosagem , Imidazóis/sangue , Lipídeos/sangue , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Macaca fascicularis , Masculino , Sulfonas/administração & dosagem , Sulfonas/sangue , Triglicerídeos/metabolismo
9.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22650305

RESUMO

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Anticolesterolemiantes/síntese química , Apolipoproteína B-100/antagonistas & inibidores , Apolipoproteína B-100/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/tratamento farmacológico , Cricetinae , Descoberta de Drogas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Ratos , Estilbenos/síntese química
10.
J Med Chem ; 52(9): 2794-8, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19351168

RESUMO

A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.


Assuntos
Androgênios , Músculos/efeitos dos fármacos , Músculos/metabolismo , Oxazóis/química , Oxazóis/farmacologia , Animais , Cristalografia por Raios X , Humanos , Concentração de Íons de Hidrogênio , Masculino , Modelos Moleculares , Conformação Molecular , Próstata/efeitos dos fármacos , Próstata/metabolismo , Ratos , Especificidade por Substrato
11.
Bioorg Med Chem Lett ; 18(14): 4072-4, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18554903

RESUMO

The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.


Assuntos
Hormônio do Crescimento/metabolismo , Ácidos Pentanoicos/síntese química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Carbamatos/farmacologia , Química Farmacêutica/métodos , Desenho de Drogas , Indóis/farmacologia , Modelos Químicos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacologia , Hormônios Peptídicos/química , Ratos , Compostos de Espiro/farmacologia , Estereoisomerismo , Tetrazóis/farmacologia
12.
Bioorg Med Chem Lett ; 18(8): 2536-9, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18378446

RESUMO

A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Hormônio do Crescimento/metabolismo , Tetrazóis/química , Amidas/química , Animais , Linhagem Celular , Glioma/metabolismo , Hormônio do Crescimento/sangue , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 18(6): 1825-9, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18295486

RESUMO

The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).


Assuntos
Desenho de Drogas , Hormônio do Crescimento/metabolismo , Serina/análogos & derivados , Tetrazóis/química , Tetrazóis/farmacologia , Animais , Carbamatos/farmacologia , Estrutura Molecular , Ratos , Serina/química , Relação Estrutura-Atividade , Tetrazóis/síntese química
15.
J Med Chem ; 50(24): 5890-3, 2007 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-17973363

RESUMO

A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.


Assuntos
Carbamatos/síntese química , Hormônio do Crescimento/metabolismo , Tetrazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Cães , Ésteres , Hormônio do Crescimento/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Macaca fascicularis , Ratos , Solubilidade , Relação Estrutura-Atividade , Tetrazóis/farmacocinética , Tetrazóis/farmacologia , Água
17.
J Med Chem ; 50(13): 3015-25, 2007 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-17552509

RESUMO

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.


Assuntos
Anabolizantes/síntese química , Imidazóis/síntese química , Músculo Esquelético/efeitos dos fármacos , Pirróis/síntese química , Receptores Androgênicos/metabolismo , Administração Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Meia-Vida , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Modelos Moleculares , Músculo Esquelético/anatomia & histologia , Orquiectomia , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
19.
Endocrinology ; 148(1): 4-12, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17008401

RESUMO

A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Músculo Esquelético/efeitos dos fármacos , Próstata/efeitos dos fármacos , Pirróis/síntese química , Pirróis/farmacologia , Receptores Androgênicos/metabolismo , Testosterona/análogos & derivados , Envelhecimento/metabolismo , Animais , Aromatase/metabolismo , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidrotestosterona/química , Di-Hidrotestosterona/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Humanos , Imidazóis/metabolismo , Ligantes , Hormônio Luteinizante/sangue , Masculino , Músculo Esquelético/fisiologia , Orquiectomia , Próstata/fisiologia , Estrutura Terciária de Proteína , Pirróis/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/química , Receptores Androgênicos/genética , Testosterona/química , Testosterona/metabolismo , Transcrição Genética/fisiologia
20.
J Med Chem ; 49(26): 7596-9, 2006 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-17181141

RESUMO

A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidantoínas/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Receptores Androgênicos/metabolismo , Administração Oral , Animais , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Células Cultivadas , Di-Hidrotestosterona/farmacologia , Humanos , Hidantoínas/administração & dosagem , Hidantoínas/síntese química , Hidantoínas/química , Luciferases/metabolismo , Masculino , Camundongos , Músculo Esquelético/crescimento & desenvolvimento , Mioblastos/efeitos dos fármacos , Ratos , Ativação Transcricional
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA