5-alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor.
Future Med Chem
; 5(17): 2037-56, 2013 Nov.
Article
en En
| MEDLINE
| ID: mdl-24215345
ABSTRACT
BACKGROUND:
Recently, we reported ethyl nicotinates as antagonists of the P2Y12 receptor, which is an important target in antiplatelet therapies. A potential liability of these compounds was their generally high in vivo clearance due to ethyl ester hydrolysis.RESULTS:
Shape and electrostatic similarity matching was used to select five-membered heterocycles to replace the ethyl ester functionality. The 5-methyl and 5-ethyl-oxazole bioisosteres retained the sub-micromolar potency levels of the parent ethyl esters. Many oxazoles showed a higher CYP450 dependent microsomal metabolism than the corresponding ethyl esters. Structure activity relationship investigations supported by ab initio calculations suggested that a correctly positioned alkyl substituent and a strong hydrogen bond acceptor were necessary structural motifs for binding. In rat pharmacokinetics, the low clearance was retained upon replacement of an ethyl ester with a 5-ethyl-oxazole.CONCLUSION:
The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Oxazoles
/
Antagonistas del Receptor Purinérgico P2Y
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Future Med Chem
Año:
2013
Tipo del documento:
Article
País de afiliación:
Suecia