SAR and species/stereo-selective metabolism of the sorbitol dehydrogenase inhibitor, CP-470,711.
SAR studies on the stereoisomers of CP-470,711 suggested that in vivo epimerization was taking place in rats. Further metabolism studies revealed that no epimerization was occurring in dogs, and that no epimerization was expected in humans. A mechanism for the in vivo epimerization is proposed involving an oxidation-reduction pathway of the secondary benzylic alcohol, in contrast to an acid/base-promoted epimerization of the same center during chemical synthesis.
Chu-Moyer
Margaret Y
MY
Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories MS8220-3095, Eastern Point Road, CT 06340, USA. margaret_y_chu-moyer@groton.pfizer.com
Ballinger
William E
WE
Beebe
David A
DA
Coutcher
James B
JB
Day
Wesley W
WW
Li
Jiancheng
J
Oates
Peter J
PJ
Weekly
R Matthew
RM
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000138:chemical synthesis / Q000378:metabolism*; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C467608:CP-470711; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D007064:L-Iditol 2-Dehydrogenase