In Vitro Metabolism of Phenoxypropoxybiguanide Analogues in Human Liver Microsomes to Potent Antimalarial Dihydrotriazines

• Published in: Journal of medicinal chemistry Vol. 48; no. 8; pp. 2805 - 2813
• Main Authors: Shearer, Todd. W, Kozar, Michael. P, O'Neil, Michael T, Smith, Philip L, Schiehser, Guy A, Jacobus, David. P, Diaz, Damaris S, Yang, Young-Sun, Milhous, Wilbur. K, Skillman, Donald. R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 21.04.2005
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemistry; Antimalarials - metabolism; Antimalarials - pharmacokinetics; Antiparasitic agents; Biguanides - chemistry; Biguanides - metabolism; Biguanides - pharmacokinetics; Biological and medical sciences; Chromatography, Liquid; Drug Resistance; Folic Acid Antagonists - pharmacology; Humans; In Vitro Techniques; Mass Spectrometry; Medical sciences; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Structure-Activity Relationship; Triazines - metabolism; Human; Protozoa; Antimalarial; Apicomplexa; Nitrogen heterocycle; Liver; Benzene derivatives; Prodrug; Microsome; Metabolism; In vitro; Antiprotozoal agent; Plasmodium falciparum; Biguanides; Structure activity relation; Proguanil; Six membered ring; Triazine derivatives; Parasiticide; Kinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049683+

Phenoxypropoxybiguanides, such as 1 (PS-15), are prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Unfortunately, manufacturing processes and gastrointestinal intolerance have prevented the clinical development of 1. In vitro antimalarial activity and in vitro metabolism studies have been performed on newly synthesized phenoxypropoxybiguanide analogues. All of the active dihydrotriazine metabolites exhibited potent antimalarial activity with in vitro IC50 values less than 0.04 ng/mL. In vitro metabolism studies in human liver microsomes identified the production of not only the active dihydrotriazine metabolite, but also a desalkylation on the carbonyl chain, and multiple hydroxylated metabolites. The V max for production of the active metabolites ranged from 10.8 to 27.7 pmol/min/mg protein with the K m ranging from 44.8 to 221 μM. The results of these studies will be used to guide the selection of a lead candidate.