RESUMO
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 amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Antagonistas de Receptores de Andrógenos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Sebo/efeitos dos fármacos , Sebo/metabolismo , Aminopiridinas/síntese química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C3H , Modelos Moleculares , Estrutura Molecular , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Peptide analogues of Tendamistat which include the most essential residues linked by novel omega-amino acids (X,Y,Z: H2N-(CH2)n-CO(2)H, where n=2-10) were designed, synthesized (Ac-Tyr(15)-X-Trp(18)-Arg(19)-Tyr(20)-Y-Thr(55)-Z-Asp(58)-Gly(59)-Tyr(60)-Ile(61)-Gly(62)-NH2), and analyzed for alpha-amylase inhibitory activity. Native dipeptide spacers sometimes were left intact at X and Z. Analogues demonstrated competitive inhibition with K(i) values ranging from 23 to 767 microM. 8-Aminooctanoic acid was the optimal linker at Y, while longer linkers were favored at the other positions.
