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1.
ACS Med Chem Lett ; 7(1): 40-5, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819663

RESUMO

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

2.
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
3.
Bioorg Med Chem Lett ; 24(15): 3268-73, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24980053

RESUMO

Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.


Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Glucocorticoides/agonistas , Tiadiazóis/farmacologia , Ureia/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Ureia/análogos & derivados , Ureia/química
4.
Bioorg Med Chem Lett ; 23(19): 5442-7, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23953070

RESUMO

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.


Assuntos
Amidas/química , Amidas/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/agonistas , Sítios de Ligação , Cristalografia por Raios X , Humanos , Indazóis/química , Indazóis/farmacologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Esteroides/química , Esteroides/farmacologia , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 23(19): 5448-51, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23916594

RESUMO

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.


Assuntos
Indazóis/síntese química , Indazóis/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Amidas/farmacologia , Humanos , Indazóis/química , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Receptores de Glucocorticoides/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Ureia/química , Ureia/farmacologia
6.
Bioorg Med Chem Lett ; 23(14): 4120-6, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23746475

RESUMO

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligações de Hidrogênio , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
7.
J Med Chem ; 54(20): 7318-33, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-21899328

RESUMO

Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de Glucocorticoides/agonistas , Tiadiazóis/síntese química , Fosfatase Alcalina/biossíntese , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Edema/tratamento farmacológico , Glutamato-Amônia Ligase/biossíntese , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Interleucina-1beta/sangue , Masculino , Modelos Moleculares , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Elementos de Resposta , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologia , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/sangue , Tirosina Transaminase/biossíntese
8.
Bioorg Med Chem Lett ; 21(15): 4633-7, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21705217
9.
J Med Chem ; 53(23): 8241-51, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21073190

RESUMO

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.


Assuntos
Amidas/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Animais , Modelos Moleculares , Ratos
10.
Bioorg Med Chem Lett ; 20(23): 6886-9, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21035336

RESUMO

The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/química , Inibidores de Proteínas Quinases/síntese química , Pirazóis/farmacologia , Animais , Cristalografia por Raios X , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
11.
J Med Chem ; 53(18): 6629-39, 2010 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-20804198

RESUMO

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirróis/síntese química , Triazinas/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Células CACO-2 , Cristalografia por Raios X , Feminino , Humanos , Ligações de Hidrogênio , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese
12.
Bioorg Med Chem Lett ; 20(19): 5864-8, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20732813

RESUMO

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Nitrogênio/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/química , Enxofre/química , Tiazóis/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Drogas , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia
13.
Bioorg Med Chem Lett ; 19(8): 2139-43, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19321341

RESUMO

A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.


Assuntos
Antracenos/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/metabolismo , Antracenos/química , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas/métodos , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/fisiologia , Relação Estrutura-Atividade
14.
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
15.
Future Med Chem ; 1(6): 1029-36, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21425992

RESUMO

Humankind has been in the business of discovering drugs for thousands of years. At present, small-molecule drug design is based on specific macromolecular receptors as targets for inhibition or modulation. To this end, a number of clever approaches have evolved over time: computer-aided techniques including structure-activity relationships and synthesis, high-throughput screening, quantitative structure-activity relationships, hypotheses derived from ligand- and/or structure-based information and focused library approaches. In recent years, several alternative strategies have appeared in the form of the emerging paradigms of polypharmacology, systems biology and personalized medicine. These innovations point to key challenges and breakthroughs likely to affect the future of small-molecule drug discovery.


Assuntos
Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Ensaios Clínicos como Assunto , Projeto Auxiliado por Computador , Humanos , Medicina Tradicional , Estrutura Molecular , Extratos Vegetais/química , Medicina de Precisão , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Biologia de Sistemas
16.
IDrugs ; 11(12): 894-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19051151

RESUMO

The concept of quantitative SAR (QSAR) is inherently imbued with an expectation of predictivity, novel insights and the generation of useful hypotheses, particularly as applied to the drug discovery process. However, even recently developed QSAR models often appear to be flawed, characterized by mediocre predictive power and undecipherable descriptors. As a result, users may be able to derive only a vague notion of which molecular features are correlated to activity. Consideration of several precautions is necessary to attempt to circumvent the misuse and misunderstanding of the QSAR technique. Issues related with QSAR include an erroneous association of correlation with causation, the close relationship between large numbers of descriptors and the effect of chance factor, the misuse of the 'leave-one-out' paradigm, and finally, the QSAR enigma, wherein the predictivity of a model is not necessarily a measure of a model's utility.


Assuntos
Desenho de Drogas , Farmacologia Clínica/tendências , Relação Quantitativa Estrutura-Atividade , Biologia Computacional , Preparações Farmacêuticas/química , Pesquisa , Descritores
17.
Bioorg Med Chem Lett ; 18(8): 2739-44, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18364256

RESUMO

A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirróis/química , Triazinas/síntese química , Triazinas/farmacologia , Amidas/química , Animais , Cristalografia por Raios X , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Triazinas/química , Fator de Necrose Tumoral alfa/biossíntese
18.
Bioorg Med Chem Lett ; 18(8): 2652-7, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18359226

RESUMO

The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/química
19.
Bioorg Med Chem Lett ; 18(6): 1762-7, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18313298
20.
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
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