title: Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogues by cytochrome P450 3A4.
abstract: Compounds that coordinate to the heme-iron of cytochrome P450 (CYP) enzymes are assumed to increase metabolic stability. However, recently we observed that the type II binding quinoline carboxamide (QCA) compounds were metabolically less stable. To test if the higher intrinsic clearance of type II binding compounds relative to type I binding compounds is general for other metabolic transformations, we synthesized a library of QCA compounds that could undergo N-dealkylation, O-dealkylation, benzylic hydroxylation, and aromatic hydroxylation. The results demonstrated that type II binding QCA analogues were metabolically less stable (2- to 12-fold) at subsaturating concentration compared to type I binding counterparts for all the transformations. When the rates of different metabolic transformations between type I and type II binding compounds were compared, they were found to be in the order of N-demethylation > benzylic hydroxylation> O-demethylation > aromatic hydroxylation. Finally, for the QCA analogues with aza-heteroaromatic rings, we did not detect metabolism in aza-aromatic rings (pyridine, pyrazine, pyrimidine), indicating that electronegativity of the nitrogen can change regioselectivity in CYP metabolism.
authors.affiliation: Department of Chemistry, Washington State University, P.O. Box 644630, Pullman, Washington 99164-4630, United States.
authors.forename: Upendra P
authors.initials: UP
authors.lastname: Dahal
authors.forename: Carolyn
authors.initials: C
authors.lastname: Joswig-Jones
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Jones
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D020134:Catalytic Domain; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry*; D065692:Cytochrome P-450 CYP3A Inhibitors; D003640:Dealkylation; D006900:Hydroxylation; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000577:Amides; D065692:Cytochrome P-450 CYP3A Inhibitors; D011719:Pyrazines; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines; D054852:Small Molecule Libraries; D051544:Cytochrome P-450 CYP3A; C030986:pyrimidine
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