SAR and species/stereo-selective metabolism of the sorbitol dehydrogenase inhibitor, CP-470,711

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 11; pp. 1477 - 1480
• Main Authors: Chu-Moyer, Margaret Y., Ballinger, William E., Beebe, David A., Coutcher, James B., Day, Wesley W., Li, Jiancheng, Oates, Peter J., Weekly, R.Matthew
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 03-06-2002; Elsevier
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Dogs; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Hepatocytes - enzymology; Humans; L-Iditol 2-Dehydrogenase - antagonists & inhibitors; L-Iditol 2-Dehydrogenase - blood; L-Iditol 2-Dehydrogenase - chemical synthesis; L-Iditol 2-Dehydrogenase - metabolism; Medical sciences; Oxidation-Reduction; Pharmacology. Drug treatments; Pyrimidines - chemistry; Pyrimidines - metabolism; Pyrimidines - pharmacology; Rats; Species Specificity; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity; Endocrinopathy; Epimerization; Rat; Nitrogen heterocycle; Structure activity relation; Secondary alcohol; Chemical synthesis; Dog; Fissipedia; Carnivora; Enzyme; Interspecific comparison; Diabetes mellitus; Rodentia; Enzyme inhibitor; Metabolism; In vitro; In vivo; Vertebrata; Mammalia; Animal; L-Iditol 2-dehydrogenase; Pyrimidine derivatives; Oxidoreductases; Piperazine derivatives; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00208-1

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.
In vivo pharmacological and drug metabolism studies revealed that CP-470,711 (
1) undergoes epimerization in rat, but not dog. In vitro studies suggest that
1 will not epimerize in humans.