RESUMO
Effective treatments of neuropathic pain have been a focus of many discovery programs. KCNQ (kv7) are voltage gated potassium channel openers that have the potential for the treatment of CNS disorders including neuropathic pain. Clinical studies have suggested agents such as Retigabine to be a modulator of pain-like effects such as hyperalgesia and allodynia. In this paper, we describe the discovery and evaluation of a series of novel pyrazolopyrimidines and their affinity for potassium channels KCNQ2/3. These pyrazolopyrimidines have also shown good efficacy in the capsaicin-induced acute and secondary mechanical allodynia model and excellent pharmacokinetic properties, which may be superior to Retigabine.
Assuntos
Desenho de Fármacos , Hiperalgesia/tratamento farmacológico , Ativação do Canal Iônico/efeitos dos fármacos , Canais de Potássio KCNQ/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Humanos , Pirazóis/química , Pirimidinas/químicaRESUMO
4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.
Assuntos
Antagonistas de Receptores de Andrógenos , Cicloexanóis/síntese química , Cicloexanóis/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Pele , Cristalografia por Raios X , Cicloexanóis/química , Desenho de Fármacos , Ligantes , Modelos Moleculares , Estrutura Molecular , Nitrilas/química , Fármacos Fotossensibilizantes/química , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Esteroides/química , Relação Estrutura-AtividadeRESUMO
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).
Assuntos
Antagonistas de Receptores de Andrógenos , Flúor/química , Nitrilas/química , Nitrilas/farmacologia , Receptores Androgênicos/metabolismo , Sebo/efeitos dos fármacos , Sebo/metabolismo , Humanos , Concentração Inibidora 50 , Metilação , Estrutura Molecular , Nitrilas/síntese química , Relação Estrutura-AtividadeRESUMO
The discovery and efficacy of a series of potent aminopyrrolidineamide-based inhibitors of sterol regulatory element binding protein site-1 protease is described.