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

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

  • J Med Chem. 2002 Jun 6;45(12):2388-409. doi: 10.1021/jm010531d.
Ian M Bell 1,  Steven N Gallicchio,  Marc Abrams,  Lorena S Beese,  Douglas C Beshore,  Hema Bhimnathwala,  Michael J Bogusky,  Carolyn A Buser,  J Christopher Culberson,  Joseph Davide,  Michelle Ellis-Hutchings,  Christine Fernandes,  Jackson B Gibbs,  Samuel L Graham,  Kelly A Hamilton,  George D Hartman,  David C Heimbrook,  Carl F Homnick,  Hans E Huber,  Joel R Huff,  Kelem Kassahun,  Kenneth S Koblan,  Nancy E Kohl,  Robert B Lobell,  Joseph J Lynch Jr,  Ronald Robinson,  A David Rodrigues,  Jeffrey S Taylor,  Eileen S Walsh,  Theresa M Williams,  C Blair Zartman
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
PMID: 12036349 DOI: 10.1021/jm010531d
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 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.

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