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1.
J Am Chem Soc ; 141(22): 8752-8757, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117664

RESUMO

We report here a catalytic method for the modular ring expansion of cyclic aliphatic alcohols. In this work, proton-coupled electron transfer activation of an allylic alcohol substrate affords an alkoxy radical intermediate that undergoes subsequent C-C bond cleavage to furnish an enone and a tethered alkyl radical. Recombination of this alkyl radical with the revealed olefin acceptor in turn produces a ring-expanded ketone product. The regioselectivity of this C-C bond-forming event can be reliably controlled via substituents on the olefin substrate, providing a means to convert a simple N-membered ring substrate to either n+1 or n+2 ring adducts in a selective fashion.

2.
Nature ; 551(7681): 489-493, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29168802

RESUMO

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.


Assuntos
Carbono/química , Hidrocarbonetos Aromáticos/química , Hidrogênio/química , Piridonas/química , Alcenos/química , Produtos Biológicos/química , Catálise , Ligantes , Paládio/química , Preparações Farmacêuticas/química
3.
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326332

RESUMO

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.

4.
Angew Chem Int Ed Engl ; 55(2): 785-9, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26611496

RESUMO

A quinoline-based ligand effectively promotes the palladium-catalyzed borylation of C(sp(3))-H bonds. Primary ß-C(sp(3))-H bonds in carboxylic acid derivatives as well as secondary C(sp(3))-H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)- and rhodium(I)-catalyzed C-H borylation reactions in terms of scope and operational conditions.


Assuntos
Compostos de Boro/química , Paládio/química , Catálise , Ligações de Hidrogênio , Ligantes
5.
Toxicol Pathol ; 43(6): 825-37, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26085543

RESUMO

Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.


Assuntos
Diabetes Mellitus/genética , Ativadores de Enzimas/toxicidade , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/toxicidade , Ratos Zucker/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus/patologia , Cães , Ingestão de Alimentos/efeitos dos fármacos , Ativadores de Enzimas/farmacocinética , Glucoquinase/genética , Hipoglicemia/patologia , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/sangue , Resistência à Insulina/genética , Masculino , Ratos , Especificidade da Espécie , Toxicocinética
6.
Bioorg Med Chem Lett ; 25(6): 1196-205, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25686852

RESUMO

The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.


Assuntos
Hipoglicemiantes/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Pirrolidinas/química , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Ligantes , Camundongos , Camundongos Obesos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
7.
Bioorg Med Chem Lett ; 20(9): 2933-7, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20356736

RESUMO

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.


Assuntos
Anti-Inflamatórios/síntese química , Glicina/análogos & derivados , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Cricetinae , Cristalografia por Raios X , Glicina/síntese química , Glicina/farmacocinética , Humanos , Masculino , PPAR alfa/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
J Med Chem ; 53(7): 2854-64, 2010 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-20218621

RESUMO

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.


Assuntos
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
9.
Bioorg Med Chem Lett ; 19(5): 1451-6, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19201606

RESUMO

The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.


Assuntos
Azóis/síntese química , Desenho de Drogas , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Azóis/farmacologia , Linhagem Celular/enzimologia , Cristalografia por Raios X , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Transgênicos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 18(12): 3545-50, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18511276

RESUMO

Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARalpha/gamma agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the alpha,beta-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.


Assuntos
Ácidos Carboxílicos , PPAR alfa/agonistas , PPAR gama/agonistas , Piperidinas , Ligação Competitiva/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 18(6): 1939-44, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291645

RESUMO

A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.


Assuntos
Azetidinas/química , Azetidinas/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Administração Oral , Animais , Azetidinas/síntese química , Disponibilidade Biológica , Cobre/farmacologia , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Diabetes Mellitus Experimental/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Glucose/metabolismo , Camundongos , Camundongos Mutantes , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Conformação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
12.
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
13.
Bioorg Med Chem Lett ; 17(21): 5928-33, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17869100

RESUMO

A novel class of Growth Hormone Secretagogues (GHS), based on a tetrazole template, has been discovered. In vitro SAR and in vivo potency within this new class of GHS are described. The tetrazole 9q exhibits good oral bioavailability in rats and dogs as well as efficacy following an oral 10 mg/kg dose in dogs. Solution and solid phase protocols for the synthesis of tetrazole based GHS have been developed.


Assuntos
Hormônio do Crescimento/metabolismo , Tetrazóis/química , Tetrazóis/farmacologia , Animais , Cães , Relação Estrutura-Atividade , Tetrazóis/síntese química
14.
Anal Biochem ; 363(2): 263-74, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17335769

RESUMO

Peroxisome proliferator-activated receptors (PPARs) and other members of the nuclear hormone receptor family are important drug targets for the treatment of metabolic diseases. PPARalpha and PPARgamma play crucial roles in lipid and glucose metabolism, respectively. Therefore, screening methods that help to rapidly identify activators of these receptors should be of considerable value. A homogeneous fluorescence polarization (FP) ligand binding assay capable of rapidly identifying ligands that bind to both PPARalpha and PPARgamma has been developed using purified PPARalpha or PPARgamma ligand binding domains and a fluorescein-labeled analog (FLA) of a potent dual PPARalpha/gamma activator. FLA activator showed good binding affinity toward both PPARalpha (K(i)=0.7microM) and PPARgamma (K(i)=0.4microM). The binding of FLA activator was rapid and reached a plateau within 10 min. The resulting FP signal was stable for at least 18h. The FP binding assay performed robustly in a 384-well format, and the average Z' value was 0.77. There was a good correlation between the binding potency (IC(50) values) and rank order of binding potency for a panel of standard PPAR ligands obtained in FP binding assay and scintillation proximity assay or gel filtration binding assays using (3)H-labeled PPARalpha (r(2)=0.99) and PPARgamma (r(2)=0.99) ligands. There was also a good correlation of IC(50) values obtained by FP binding assay and scintillation proximity assay for the clinically used PPAR activators. Thus, the FP binding assay with a single fluorescein-labeled PPARalpha/gamma dual activator offers a homogeneous nonradioactive, sensitive, robust, and less expensive high-throughput assay for detecting compounds that bind to both PPARgamma and PPARalpha. Using this FP binding assay, we have identified a large number of PPARalpha/gamma dual activators. A similar assay platform may be easily adapted to other members of the nuclear hormone receptor family.


Assuntos
Polarização de Fluorescência/métodos , Ligantes , PPAR alfa/metabolismo , PPAR gama/metabolismo , Cromatografia em Gel , Dimetil Sulfóxido/química , Humanos , Cinética , Modelos Biológicos , Estrutura Molecular , PPAR alfa/agonistas , PPAR alfa/genética , PPAR gama/agonistas , PPAR gama/genética , Ligação Proteica , Reprodutibilidade dos Testes
16.
Chirality ; 18(9): 746-53, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16856170

RESUMO

Compound A, a novel disubstituted pyrrolidine acid, is a member of a new class of agents that are potentially useful for the treatment of diabetes and dyslipidemia. The absolute configuration of this compound was determined by using vibrational circular dichroism (VCD). The results are in agreement with the assignments based on both X-ray analysis and the stereo-selective chemical synthesis. During VCD analysis, the solution conformation for a portion of compound A in CDCl(3) was also established. The compound is found to associate as an H-bonded carboxylic acid "dimer" in CDCl(3) solution, and VCD calculations on a model dimer fragment were required to establish the absolute configuration.


Assuntos
Ácidos/análise , Ácidos/química , Dicroísmo Circular/métodos , Pirrolidinas/análise , Pirrolidinas/química , Dimerização , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Soluções/química , Espectrofotometria Infravermelho , Estereoisomerismo
17.
Mini Rev Med Chem ; 5(8): 741-53, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16101410

RESUMO

Peroxisome proliferator-activated receptors (PPARs) alpha, gamma and delta (beta) are ligand-activated transcription factors of the nuclear hormone receptor superfamily which have been shown to play key roles in maintaining glucose and lipid homeostasis. The physiological effects of several marketed drugs for the treatment of dyslipidemia (fenofibrate and gemfibrozil) and diabetes (rosiglitazone and pioglitazone) have now been shown to be mediated through PPARalpha and PPARgamma respectively. Over the past few years our understanding of how PPAR ligands and receptors modulate gene expression has greatly increased; this knowledge is being used to design even more potent and efficacious PPAR ligands for the treatment of diabetes, dyslipidemia, atherosclerosis and obesity. This review is a brief survey of the PPAR field which highlights recent progress, with an emphasis on new ligands with novel PPAR profiles, particularly compounds which are co-agonists of PPAalpha, gamma and beta (delta).


Assuntos
Antimetabólitos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Homeostase/efeitos dos fármacos , Doenças Metabólicas/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Animais , Doenças Cardiovasculares/metabolismo , Sistemas de Liberação de Medicamentos , Glucose/metabolismo , Homeostase/fisiologia , Humanos , Ligantes , Metabolismo dos Lipídeos , Doenças Metabólicas/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Fatores de Transcrição/metabolismo
18.
J Med Chem ; 48(6): 2248-50, 2005 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-15771468

RESUMO

Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.


Assuntos
Glicina/análogos & derivados , Glicina/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Oxazóis/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Adipócitos/citologia , Animais , Glicemia/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos/sangue , Glicina/química , Glicina/farmacologia , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Insulina/sangue , Masculino , Camundongos , Camundongos Obesos , Oxazóis/química , Oxazóis/farmacologia , Ativação Transcricional , Triglicerídeos/sangue
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