RESUMO
Structure-activity relationship (SAR) studies of novel 5-alkyl and 5-aryl/heteroaryl substituted 1,2,4-triazoles are described. The in vitro activity is compared to the pyrazole class of compounds with analogous side chains to delineate the contribution of the triazole ring nitrogen in binding to the active site. Both series are quite potent and selective in the canine whole blood (CWB) COX-2 assay, suggesting the increased binding contribution of the hydrophobic side chains.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Éteres/química , Pirazóis/síntese química , Pirazóis/farmacologia , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Alquilação , Animais , Inibidores de Ciclo-Oxigenase 2/sangue , Inibidores de Ciclo-Oxigenase 2/química , Cães , Concentração Inibidora 50 , Estrutura Molecular , Pirazóis/sangue , Pirazóis/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/química , Triazóis/sangue , Triazóis/químicaRESUMO
Careers in the pharmaceutical industry were revealed in modules facilitated by senior scientists from companies that sponsor the Cornell Leadership Program for Veterinary Students. One module was structured as a series of interviews for different positions in industry, the other as a competition between hypothetical companies created by students. The interview-based module stimulated wide-ranging discussion of the activities and responsibilities of veterinarians employed in a discovery-intensive pharmaceutical firm and of the characteristics such companies seek in prospective employees, from both professional and personal perspectives. The second module explored the drug discovery and development process from the perspective of animal-health companies that are competitors in the market for animal health care products. The exercise provided insights into the manner in which companies discover new chemical entities, screen candidate drugs, allocate resources, and pursue the development of products through testing, licensing, and distribution.
Assuntos
Educação em Farmácia , Educação em Veterinária , Estudantes/psicologia , Drogas Veterinárias , Animais , Escolha da Profissão , Currículo , Humanos , Liderança , Faculdades de Medicina VeterináriaRESUMO
The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Celecoxib , Ciclo-Oxigenase 1/metabolismo , Cães , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Técnicas In Vitro , Indicadores e Reagentes , Cinética , Modelos Moleculares , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
The synthesis of a novel gut selective MTP inhibitor, 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), and its in vitro and in vivo profile are described. Dirlotapide (3) demonstrated excellent potency against MTP enzyme in HepG2 cells and canine hepatocytes. This novel MTP inhibitor also showed excellent efficacy when tested in a canine food intake model.
Assuntos
Carbamatos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntese química , Proteínas de Transporte/antagonistas & inibidores , Química Farmacêutica/métodos , Indóis/síntese química , Obesidade/tratamento farmacológico , Animais , Carbamatos/química , Carbamatos/farmacologia , Ácidos Carboxílicos/farmacologia , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , RatosRESUMO
We have successfully identified a number of novel MTP inhibitors with single digit nanomolar potency. Analogues 10aq and 10dq demonstrated in vivo efficacy in a murine gut retention assay.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/química , Proteínas de Transporte/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.
Assuntos
Inibidores de Ciclo-Oxigenase 2 , Ciclo-Oxigenase 2/efeitos dos fármacos , Pirazóis , Administração Oral , Animais , Gatos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl(thio)ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivatives for canine COX enzymes are described. The 4-cyano-5-alkyl ethers were found to have excellent potency and selectivity, whereas the 5-thioethers were potent but less selective than the ether analogs in a canine whole blood (CWB) COX-2 assay.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Éteres/química , Pirazóis/química , Compostos de Sulfidrila/química , Alquilação , Animais , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Cães , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure-activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12 nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Pirazóis/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Cães , Concentração Inibidora 50 , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis of a novel canine COX-2 selective inhibitor, 2-(3-difluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, and its in vitro and in vivo profile are described. Pyrazole 8 demonstrated excellent potency and selectivity for canine COX-2 in both in vitro and ex vivo whole blood assays. This novel COX-2 inhibitor also showed a good pharmacokinetic profile (pk) following oral (po), intravenous (iv), and subcutaneous (sc) dosing and demonstrated excellent in vivo efficacy in a canine synovitis model.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Cães , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Pirazóis/síntese química , Piridinas/síntese químicaRESUMO
Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.