RESUMEN
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.
Asunto(s)
Aminoácidos/química , Inhibidores Enzimáticos/química , Péptidos , Péptidos/química , alfa-Amilasas/antagonistas & inhibidores , Inhibidores Enzimáticos/metabolismo , Humanos , Estructura Molecular , Péptidos/síntesis química , Péptidos/metabolismo , Unión Proteica , alfa-Amilasas/metabolismoRESUMEN
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.
Asunto(s)
Antagonistas de Receptores Androgénicos , Ciclohexanoles/síntesis química , Ciclohexanoles/farmacología , Nitrilos/síntesis química , Nitrilos/farmacología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacología , Piel , Cristalografía por Rayos X , Ciclohexanoles/química , Diseño de Fármacos , Ligandos , Modelos Moleculares , Estructura Molecular , Nitrilos/química , Fármacos Fotosensibilizantes/química , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Esteroides/química , Relación Estructura-ActividadRESUMEN
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.