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

Journal Article (Journal Article)

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 vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.

Full Text

Duke Authors

Cited Authors

  • Bell, IM; Gallicchio, SN; Abrams, M; Beese, LS; Beshore, DC; Bhimnathwala, H; Bogusky, MJ; Buser, CA; Culberson, JC; Davide, J; Ellis-Hutchings, M; Fernandes, C; Gibbs, JB; Graham, SL; Hamilton, KA; Hartman, GD; Heimbrook, DC; Homnick, CF; Huber, HE; Huff, JR; Kassahun, K; Koblan, KS; Kohl, NE; Lobell, RB; Lynch, JJ; Robinson, R; Rodrigues, AD; Taylor, JS; Walsh, ES; Williams, TM; Zartman, CB

Published Date

  • June 6, 2002

Published In

Volume / Issue

  • 45 / 12

Start / End Page

  • 2388 - 2409

PubMed ID

  • 12036349

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm010531d


  • eng

Conference Location

  • United States