3-Aminopyrrolidinone Farnesyltransferase Inhibitors:  Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

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.

Structural analysis of DNA–PKcs: modelling of the repeat units and insights into the detailed molecular architecture

“…Structural profiles of the following helical repeat proteins were taken: protein phosphatase 2A PR65/A subunit (1b3ua) , importin b (1qgra) (Cingolani et al, 1999), b-catenin (1i7wa) (Graham et al, 2000), importin a (1iala) (Teh et al, 1999), karyopherin a (1bk6a) (Conti et al, 1998), Pex5 (1fcha) (Gatto et al, 2000), TPR1 domain of Hop (1elwa) (Scheufler et al, 2000), human farnesyl transferase (1ld8a) (Bell et al, 2002;Park et al, 1997), rat farnesyl transferase (1d8da) (Long et al, 2000), transcription factor MalT domain III (1hz4) (Steegborn et al, 2001), pumilio homology domain (1ib2a) (Wang et al, 2001), B-cell lymphoma encoded protein (1kla) (Michel et al, 2001), lipid binding protein lipovitellin (1lsh) (Thompson and Banaszak, 2002), sec 17 vesicular transport protein (1qqe) (Rice and Brunger, 1999), and leucine-rich repeat variant protein (1lrv) (Peters et al, 1996). The coordinates of each were split into a number of files each containing a single repeat unit.…”

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

“…In FTase, L-778123 binds in the peptidebinding site, whereas in GGTase-I, it binds in the lipid-binding site, suggesting different mechanisms of action regarding these two enzymes, whose difference remains less understood [40]. U49 is a nonpeptide FTase inhibitor containing a macrocyclic aminopyrrolidinone scaffold [41]. Structures are depicted in Fig.…”

Inhibition of farnesyltransferase: A rational approach to treat cancer?

“…Members of this class of FTIs exhibited the highest cell potency yet described for inhibitors of FTase. Compound 10, for example inhibited the processing of HDJ2 in PSN-1 cells with an EC 50 value of 180 pM [48].…”