RESUMEN
A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.
Asunto(s)
Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Obesidad/tratamiento farmacológico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Animales , Fármacos Antiobesidad/química , Disponibilidad Biológica , Dieta , Modelos Animales de Enfermedad , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Conformación Molecular , Piperazinas/química , Ratas , EstereoisomerismoRESUMEN
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Enfermedades Autoinmunes/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.