Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogues by cytochrome P450 3A4

Upendra P Dahal; Carolyn Joswig-Jones; Jeffrey P Jones

doi:10.1021/jm201207h

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Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogues by cytochrome P450 3A4

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Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogues by cytochrome P450 3A4

Upendra P Dahal, Carolyn Joswig-Jones and Jeffrey P Jones

Journal of medicinal chemistry, Vol.55(1), pp.280-290

01/12/2012

DOI: https://doi.org/10.1021/jm201207h

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https://hdl.handle.net/2376/101949

PMCID: PMC3257383

PMID: 22087535

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Abstract

Catalytic Domain

Hydroxylation

Amides - chemical synthesis

Pyridines - chemistry

Pyrimidines - chemical synthesis

Dealkylation

Quinolines - chemistry

Pyridines - chemical synthesis

Substrate Specificity

Structure-Activity Relationship

Pyrazines - chemical synthesis

Pyrimidines - chemistry

Quinolines - chemical synthesis

Pyrazines - chemistry

Cytochrome P-450 CYP3A Inhibitors

Small Molecule Libraries

Cytochrome P-450 CYP3A - chemistry

Amides - chemistry

Protein Binding

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.

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Title: Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogues by cytochrome P450 3A4
Creators: Upendra P Dahal - Department of Chemistry, Washington State University, P.O. Box 644630, Pullman, Washington 99164-4630, United States
Carolyn Joswig-Jones
Jeffrey P Jones
Publication Details: Journal of medicinal chemistry, Vol.55(1), pp.280-290
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 GM084546 / NIGMS NIH HHS R01 GM084546-14 / NIGMS NIH HHS GM84546 / NIGMS NIH HHS
Identifiers: 99900546504701842
Language: English
Resource Type: Journal article