Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4 …

…, N McDowall, CB Jones, CJR Hedgecock…

Index: Kuo, Elizabeth A.; Hambleton, Philip T.; Kay, David P.; Evans, Phillip L.; Matharu, Saroop S.; Little, Edward; McDowall, Neil; Jones, C. Beth; Hedgecock, Charles J. R.; Yea, Christopher M.; Chan, A. W. Edith; Hairsine, Peter W.; Ager, Ian R.; Tully, W. Roger; Williamson, Richard A.; Westwood, Robert Journal of Medicinal Chemistry, 1996 , vol. 39, # 23 p. 4608 - 4621

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Citation Number: 88

Abstract

The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in ...