5-alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor.
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.


CONCLUSIONS
The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.
Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, S-43183 Mölndal, Sweden.
Peter
P
Bach
Jonas
J
Boström
Kay
K
Brickmann
Laurence E
LE
Burgess
David
D
Clarke
Robert D
RD
Groneberg
Darren M
DM
Harvey
Ellen R
ER
Laird
Michael
M
O'Sullivan
Fredrik
F
Zetterberg
D000818:Animals; D006801:Humans; D006860:Hydrogen Bonding; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D010080:Oxazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D010080:Oxazoles; D058921:Purinergic P2Y Receptor Antagonists