PT  - JOURNAL ARTICLE
AU  - Madoka Suzuki
AU  - Yutai Li
AU  - Philip C. Smith
AU  - James A. Swenberg
AU  - David E. Martin
AU  - Susan L. Morris-Natschke
AU  - Kuo-Hsiung Lee
TI  - ANTI-AIDS AGENTS 65: INVESTIGATION OF THE IN VITRO OXIDATIVE METABOLISM OF 3′,4′-DI-<em>O</em>-(–)-CAMPHANOYL-(+)-<em>CIS</em>-KHELLACTONE DERIVATIVES AS POTENT ANTI-HIV AGENTS
AID  - 10.1124/dmd.105.004218
DP  - 2005 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1588--1592
VI  - 33
IP  - 11
4099  - http://dmd.aspetjournals.org/content/33/11/1588.short
4100  - http://dmd.aspetjournals.org/content/33/11/1588.full
SO  - Drug Metab Dispos2005 Nov 01; 33
AB  - 3′,4′-Di-O-(–)-camphanoyl-(+)-cis-khellactone (DCK) is a synthetic khellactone ester that exhibits potent in vitro anti-human immunodeficiency virus (HIV) activity with a mechanism distinct from clinically used anti-HIV agents. Several series of mono- and di-substituted DCK derivatives (DCKs) have previously been synthesized, and their structure-activity relationships are well established. To optimize DCK as a drug lead and to guide further structural modifications, metabolic stabilities and metabolite structures were analyzed. In vitro metabolic stabilities of DCKs in human liver microsomes were assessed using high performance liquid chromatography (HPLC) with UV detection to establish structure-metabolism relationships (SMRs). HPLC coupled with ion trap mass spectrometry was used to identify the metabolite structures. The results indicated that DCKs undergo rapid oxidation on the lipophilic camphanoyl moieties and the substituents on the khellactone do not alter the rate or the metabolic pathways for this compound type. Our SMR and metabolite analysis study suggested that the two camphanoyl ester moieties are the determinants of the low metabolic stability and that structural alteration in the two esters may be necessary to improve metabolic profiles of DCKs. The American Society for Pharmacology and Experimental Therapeutics