Identification of Pharmacokinetically Stable 3,10-Dibromo-8-chlorobenzocycloheptapyridine Farnesyl Protein Transferase Inhibitors with Potent Enzyme and Cellular Activities

Abstract

Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

Farnesyl Transferase Inhibitors: Mechanism of Action, Translational Studies and Clinical Evaluation

“…39 SCH 66336 does not inhibit geranylgeranyl transferase-1 at concentrations up to 20 micromolar. Compounds in the tricyclic series compete with the CAAX peptide substrate 38 and overlap with the CAAX peptide binding site in the farnesyl transferase crystal structure.…”

Exploring Structure-Activity Relationships of Tricyclic Farnesyltransferase Inhibitors Using ECLiPS® Libraries

“…Despite their relatively large size, the tricyclic FTIs have surprisingly acceptable pharmacokinetic profiles [26,37]. The FT-2 resynthesized compounds appear to be no exception.…”

“…This compound, along with its predecessors and subsequent analogs, have been extensively characterized [22][23][24][25][26][27][28]. The steady progression of SCH 66336 through the clinic has sustained the search for a back-up compound that could follow in its footsteps.…”

Inhibiting Fornesyl Protein Transferase with Sch-66336: Potentially a Selective, Noncytotoxic Therapy for Human Cancer

“…Piperidylacetyl analogs of mono-and dihalo-benzocycloheptapyridine FTIs have previously been identified and found to be equi-potent with pyridyl N-oxide FTIs similar to 7 while demonstrating superior pharmacokinetic stability (30). Thus, significant modifications (Table I) of the terminal portion of 3,8,10-trihalobenzocycloheptapyridine FTIs were undertaken to identify structures with improved pharmacokinetic profiles while maintaining potencies in enzyme and cellular assays (36). Of the many analogs prepared, nicotinic N-oxides 17 and 18 demonstrated good AUCs when orally administered to mice (Table I) Although trihalobenzocycloheptapyridines demonstrated single digit nanomolar potency against FPT, their activity in cellular assays was not predictable (26).…”

“…Sulfonamide analogs (i.e., 15) were rarely bioavailable while urea Sch-66336 and oxalamide 16 demonstrated good serum concentrations in mice when dosed orally. Pharmacokinetic evaluation of Sch-66336 showed(26,36) serum concentrations of 1.9 μΜ (Cmax) and an AUC of 22 μΜ.Ιιτ in orally-treated cynomolgus monkeys (10 mpk).…”