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1.
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
2.
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
3.
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
4.
Bioorg Med Chem Lett ; 17(15): 4131-4, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17543524

RESUMO

Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.


Assuntos
Aminoácidos/farmacologia , Mimetismo Molecular , Éteres Fenílicos/farmacologia , Fenilacetatos/farmacologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Aminoácidos/química , Animais , Células CHO , Colesterol na Dieta/administração & dosagem , Cricetinae , Cricetulus , Ligantes , Ensaio Radioligante , Ratos , Receptores dos Hormônios Tireóideos/metabolismo
6.
Bioorg Med Chem Lett ; 15(20): 4579-84, 2005 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16099653

RESUMO

High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.


Assuntos
Naftalenos/química , Receptores dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade , Hormônios Tireóideos/química
7.
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
8.
Bioorg Med Chem Lett ; 14(13): 3549-53, 2004 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-15177471

RESUMO

A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity.


Assuntos
Receptores beta dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/química , Tri-Iodotironina/química , 2-Propanol/química , Aminoácidos/química , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Desenho de Drogas , Concentração Inibidora 50 , Ligantes , Relação Estrutura-Atividade , Receptores beta dos Hormônios Tireóideos/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/farmacologia , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia
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