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5-alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor.
- Source :
-
Future medicinal chemistry [Future Med Chem] 2013 Nov; Vol. 5 (17), pp. 2037-56. - Publication Year :
- 2013
-
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.<br />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.<br />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.
- Subjects :
- Animals
Humans
Hydrogen Bonding
Microsomes metabolism
Models, Molecular
Oxazoles metabolism
Oxazoles pharmacokinetics
Purinergic P2Y Receptor Antagonists metabolism
Purinergic P2Y Receptor Antagonists pharmacokinetics
Rats
Structure-Activity Relationship
Oxazoles chemistry
Oxazoles pharmacology
Purinergic P2Y Receptor Antagonists chemistry
Purinergic P2Y Receptor Antagonists pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1756-8927
- Volume :
- 5
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Future medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24215345
- Full Text :
- https://doi.org/10.4155/fmc.13.171