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Nature ; 551(7681): 489-493, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29168802


The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Carbono/química , Hidrocarbonetos Aromáticos/química , Hidrogênio/química , Piridonas/química , Alcenos/química , Produtos Biológicos/química , Catálise , Ligantes , Paládio/química , Preparações Farmacêuticas/química
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326332


BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

Drug Metab Dispos ; 39(1): 123-31, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20876787


Muraglitazar and peliglitazar, two structural analogs differing by a methyl group, are dual peroxisome proliferator-activated receptor-α/γ activators. Both compounds were extensively metabolized in humans through acyl glucuronidation to form 1-O-ß-acyl glucuronide (AG) metabolites as the major drug-related components in bile, representing at least 15 to 16% of the dose after oral administration. Peliglitazar AG was the major circulating metabolite, whereas muraglitazar AG was a very minor circulating metabolite in humans. Peliglitazar AG circulated at lower concentrations in animal species than in humans. Both compounds had a similar glucuronidation rate in UDP-glucuronic acid-fortified human liver microsomal incubations and a similar metabolism rate in human hepatocytes. Muraglitazar AG and peliglitazar AG were chemically synthesized and found to be similarly oxidized through hydroxylation and O-demethylation in NADPH-fortified human liver microsomal incubations. Peliglitazar AG had a greater stability than muraglitazar AG in incubations in buffer, rat, or human plasma (pH 7.4). Incubations of muraglitazar AG or peliglitazar AG in plasma produced more aglycon than acyl migration products compared with incubations in the buffer. These data suggested that the difference in plasma stability, not differences in intrinsic formation, direct excretion, or further oxidation of muraglitazar AG or peliglitazar AG, contributed to the observed difference in the circulation of these AG metabolites in humans. The study demonstrated the difficulty in doing risk assessment based on metabolite exposure in plasma because the more reactive muraglitazar AG would not have triggered a threshold of concern based on the recent U.S. Food and Drug Administration guidance on Metabolites in Safety Testing, whereas the more stable peliglitazar AG would have.

Glucuronídeos/sangue , Glicina/análogos & derivados , Oxazóis/metabolismo , Adulto , Animais , Bile/química , Bile/metabolismo , Estabilidade de Medicamentos , Glucuronídeos/metabolismo , Glicina/sangue , Glicina/química , Glicina/metabolismo , Glicina/farmacologia , Hepatócitos/metabolismo , Humanos , Macaca fascicularis , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Oxazóis/sangue , Oxazóis/química , Oxazóis/farmacologia , Oxirredução , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gama/agonistas , PPAR gama/metabolismo , Ratos , Medição de Risco , Uridina Difosfato Ácido Glucurônico/metabolismo , Adulto Jovem
J Med Chem ; 53(7): 2854-64, 2010 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-20218621


An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

Descoberta de Drogas , Glicina/análogos & derivados , Oxazóis/química , Oxazóis/farmacologia , PPAR alfa/agonistas , Animais , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Glicina/toxicidade , Humanos , Masculino , Camundongos , Modelos Moleculares , Oxazóis/síntese química , Oxazóis/toxicidade , PPAR alfa/química , PPAR alfa/genética , Estrutura Terciária de Proteína , Especificidade por Substrato , Ativação Transcricional/efeitos dos fármacos
Bioorg Med Chem Lett ; 18(6): 1825-9, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18295486


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).

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
J Med Chem ; 50(24): 5890-3, 2007 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-17973363


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.

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