Pure zyxwvutsrqpon & Appl. Chem., zyxwvutsrq Vol. 68, zyxwvutsr No. 3, pp. 753-756, 1996. Printed in Great Britain. Q 1996 IUPAC Metalloporphyrins as chemical mimics of cytochrome P-450 systems zyxw Mukund S. Chorghade*, David R. Hill, Elaine C. Lee and Richard J. zyxw Pariza Dept. 54P, Abbott Laboratories, North Chicago, Illinois 60064, USA David H. Dolphin, Fumio Hino and Li-Ying Zhang University of British Columbia, Vancouver, British Columbia, V6T 1Y6, Canada Abstract: Certain synthetic metalloporphyrins have been shown to mimic the zy in vivo metabolism of some pharmaceuticals. Oxidation, hydroxylation and N-demethylation yielded synthetic metabolites. If found to be general, this lays the foundation of a predictive basis to optimize analog design of inhibitors with reduced oxidative reactivity, to determine the proclivity of drugs to form biologically active metabolites and provides a convenient methodology for their preparation. Introduction: In humans and other animals, most drugs are metabolized in the liver. Many drug metabolites are formed by oxidative mechanisms catalyzed primarily by heme and cytochrome containing enzymes. Most biological oxidations involve primary catalysis provided by the cytochrome P-450 mono- oxygenase enzymes. All heme proteins that are activated by hydrogen peroxide, including catalases, peroxidases and ligninases function via a two electron oxidation of the femc resting state to an oxoferryl porphyrin x-cation radical (I).* H202 H,O 0 Fe(III)porphyrin :e(N)porphyrin+* I While this oxidation state has yet to be characterized for the cytochromes P-450, most of their reactions and those of the biomimetic analogs can be accounted for by oxygen transfer from (I) to a variety of substrates to give characteristic reactions such as hydroxylation, epoxidation and heteroatom oxidation.2 Other products resulting from hydroxyl and hydroperoxyl radicals have also been detected. The metabolic processes in vivo contribute in substantial measure to the efficacy, side effects and also the toxicity of a pharmaceutical entity. These factors are responsible for the success of failure of a clinical candidate. Metabolic processes of drugs are always the subject of intense scrutiny in pharmaceutical companies. Pharmacologistshave traditionally been involved with isolation and identification of the metabolites of a drug. It is imperative to conduct such studies early in the drug development process. Toxicological and pharmacological studies on the metabolites form a crucial segment in the identification of a clinical candidate. Current problems: Several problems are currently associated with the use of biological systems in studying drug metabolism: (i) In zyxwvutsrqpo vitro studies produce very small quantities of the product. Primary metabolites are often hydrophilic and difficult to isolate. (ii) Animal studies necessitate the sacrifice of animals and are extremely expensive to conduct. Liver slice preparations are of variable potency; it is difficult to quantitate the precise stoichiometry of the oxidant. (iii) Pharmacologists do not know, in advance, the structure of the metabolites they should seek. (iv) Many of the metabolites are not amenable to organic synthesis by conventional routes. We therefore turned to the metalloporphyrins as mimics of the in vivo metabolic processes. 753