title: Species-specific, P450- and sulfotransferase-mediated novel ring contraction of a naphthyridine-N-oxide compound in cynomolgus monkey.
abstract: BMS-A78277 (1) is a 5,10-dihydrobenzo[beta][1,8]naphthyridine-N-oxide compound that resides in a class of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), displaying improved activity against clinically relevant mutants of HIV-1 and possessing pharmacokinetic profiles amenable to once-daily dosing. In the course of investigating the nonclinical metabolism of 1, a circulating metabolite specific to the cynomolgus monkey was identified and subsequently characterized as the carboxyindole metabolite 2. The present investigation describes the biotransformation of this NNRTI in cynomolgus monkey, one which results in a net ring contraction of 1. The use of mass spectrometry and high field NMR analysis aided in the structural characterization of metabolite 2, the source of which originated from the urine and bile of cynomolgus monkeys receiving oral doses of 1. Preparation of a synthetic standard of 2 not only provided ultimate structural confirmation but also afforded ample material for biological testing. The metabolism of 1 was investigated in monkey hepatocytes and hepatic subcellular fractions. While microsomes were incapable of generating metabolite 2, incubation of 1 in monkey S9 fractions as well as hepatocytes resulted in measurable levels of the carboxyindole metabolite. Consequently, incubation of 1 in monkey hepatocytes, which were suspended in media containing (18)O-labeled water, resulted in the incorporation of (18)O into the carboxyindole metabolite, 2. These data implicate a mechanism involving the bioactivation of 1 to an electrophilic intermediate that upon hydrolysis undergoes a concerted ring contraction, resulting in the formation of 2. Previously confined to discussions regarding the metabolism of natural products and select aliphatic heterocycles, the present investigation extends the discussion of metabolism-mediated ring contraction to aromatics such as the present naphthyridine compound, 1.
authors.affiliation: Department of Metabolism, Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA. scott.daniels@pfizer.com
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Robert
authors.initials: R
authors.lastname: Espina
authors.forename: Kevin
authors.initials: K
authors.lastname: Cao
authors.forename: Haodan
authors.initials: H
authors.lastname: Yuan
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lin
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.forename: Barry
authors.initials: B
authors.lastname: Johnson
authors.forename: James
authors.initials: J
authors.lastname: Rodgers
authors.forename: Shimoga
authors.initials: S
authors.lastname: Prakash
authors.forename: Steve
authors.initials: S
authors.lastname: Unger
authors.forename: David
authors.initials: D
authors.lastname: Christ
authors.forename: Gerald
authors.initials: G
authors.lastname: Miwa
authors.forename: Liang-Shang
authors.initials: LS
authors.lastname: Gan
authors.forename: Abdul
authors.initials: A
authors.lastname: Mutlib
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004285:Dogs; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009287:Naphthyridines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity; D015238:Sulfotransferases / Q000502:physiology*
chemical_list: C525783:5,10-dihydrobenzo(beta)(1,8)naphthyridine-N-oxide; D019380:Anti-HIV Agents; D003497:Cyclic N-Oxides; D009287:Naphthyridines; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D015238:Sulfotransferases