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

…, M Ellis-Hutchings, C Fernandes…

Index: Bell, Ian M.; Gallicchio, Steven N.; Abrams, Marc; Beese, Lorena S.; Beshore, Douglas C.; Bhimnathwala, Hema; Bogusky, Michael J.; Buser, Carolyn A.; Culberson, J. Christopher; Davide, Joseph; Ellis-Hutchings, Michelle; Fernandes, Christine; Gibbs, Jackson B.; Graham, Samuel L.; Hamilton, Kelly A.; Hartman, George D.; Heimbrook, David C.; Homnick, Carl F.; Huber, Hans E.; Huff, Joel R.; Kassahun, Kelem; Koblan, Kenneth S.; Kohl, Nancy E.; Lobell, Robert B.; Lynch Jr., Joseph J.; Robinson, Ronald; Rodrigues, A. David; Taylor, Jeffrey S.; Walsh, Eileen S.; Williams, Theresa M.; Zartmant, C. Blair Journal of Medicinal Chemistry, 2002 , vol. 45, # 12 p. 2388 - 2409

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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 ...