title: A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5'-diphospho-glucuronosyltransferase metabolism profile.
abstract: Research efforts on the human immunodeficiency virus (HIV) integrase have resulted in two approved drugs. However, co-infection of HIV with Mycobacterium tuberculosis and other microbial and viral agents has introduced added complications to this pandemic, requiring favorable drug-drug interaction profiles for antiviral therapeutics targeting HIV. Cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) are pivotal determining factors in the occurrence of adverse drug-drug interactions. For this reason, it is important that anti-HIV agents, such as integrase inhibitors, possess favorable profiles with respect to CYP and UGT. We have discovered a novel HIV integrase inhibitor (compound 1) that exhibits low nM antiviral activity against a diverse set of HIV-1 isolates, and against HIV-2 and the simian immunodeficiency virus (SIV). Compound 1 displays low in vitro cytotoxicity and its resistance and related drug susceptibility profiles are favorable. Data from in vitro studies revealed that compound 1 was not a substrate for UGT isoforms and that it was not an inhibitor or activator of key CYP isozymes.
authors.affiliation: The Center for Drug Discovery and the College of Pharmacy University of Georgia, Athens, GA 30602, USA.
authors.forename: Maurice O
authors.initials: MO
authors.lastname: Okello
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mishra
authors.forename: Malik
authors.initials: M
authors.lastname: Nishonov
authors.forename: Marie K
authors.initials: MK
authors.lastname: Mankowski
authors.forename: Julie D
authors.initials: JD
authors.lastname: Russell
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wei
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Hogan
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: Vasu
authors.initials: V
authors.lastname: Nair
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D014453:Glucuronosyltransferase / Q000378:metabolism*; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D009154:Mutation; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000378:metabolism
chemical_list: C580899:(Z)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide; D019428:HIV Integrase Inhibitors; D007527:Isoenzymes; D011725:Pyridines; D011759:Pyrrolidines; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D019427:HIV Integrase