3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency

…, MJ Bogusky, CA Buser, JC Culberson…

Index: Dinsmore; Bogusky; Culberson; Bergman; Homnick; Zartman; Mosser; Schaber; Robinson; Koblan; Huber; Graham; Hartman; Huff; Williams Journal of the American Chemical Society, 2001 , vol. 123, # 9 p. 2107 - 2108

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Citation Number: 86

Abstract

A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in ...