3-Aminopyrrolidinone Farnesyltransferase Inhibitors: Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency
Citations Over TimeTop 10% of 2002 papers
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.
Related Papers
- → J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation In Vivo in a Farnesyl Pyrophosphate-Competitive Manner(1998)37 cited
- → Identification of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis from a pepticinnamin E library(2003)19 cited
- → Synthesis and biological activity of semipeptoid farnesyltransferase inhibitors(1997)14 cited
- → Synthesis and evaluation of homofarnesoyl-substituted CAAX-peptidomimetics as farnesyltransferase inhibitors and antiproliferative agents(1999)2 cited
- Farnesyltransferase Inhibitor의 세포주기억제를 통한 항암작용 기전에 관한 연구(2001)