Miscellaneous heterocyclic systems 351 Benzimidazoles

Benzimidazole-pyridones were among the early small molecule chemo-types described as ATP-competitive inhibitors of IGF-1R. The initial screening hit was optimized for potency and Cytochrome p-450 (CYP) inhibition to provide an early lead structure, BMS-536924, 21 [52-60]. This compound inhibits both IGF-1R and IR with equal potency (IC50 = 120 nM), is selective versus other kinases, inhibits the phosphorylation of Akt and MAP kinase (MAPK) in cells, and blocks proliferation in a wide variety of human cancer cell lines including colon, breast, lung, pancreas, prostate, sarcoma, and multiple myeloma (IC50's of 110-460 nM). Tumor growth inhibition is observed in vivo when dosed orally in the IGF-1R Sal tumor model [46] and in a broad range of human tumor xenografts such as Colo205, Geo, and RD1 (50-100 mg/kg). Oral bioavailability is observed across all species, and a twofold window between antitumor efficacy and glucose elevation at the efficacious dose was reported [55]. Benzimidazole 21 reverses IGF-1R-induced transformation of mammary epithelial cells, blocks proliferation, and restores apical-basal polarity in MCF-7 cells [56].

The potential for CYP inhibition, time-dependent CYP inhibition, and pregnane X receptor (PXR) transactivation was reduced by replacing the morpholine ring in 21 with a C-linked piperidine. Combining this modification with the chloropyrazole side chain [57] led to the discovery of BMS-695735, 22, which demonstrates in vivo efficacy in the IGF-Sal, Colo205, Geo colon carcinoma, and JJN3 multiple myeloma models when administered orally at doses between 50 mg/kg and 100 mg/kg [59].

3.5.2 Bicyclic pyrazoles

The patent literature also describes bicyclic pyrazole inhibitors of IGF-1R. These structures represent a significant departure from other reported leads. Limited IGF-1R activity is presented in these patents with 23 being the most potent example reported (IC50 = 49 nM) [61-63].

3.5.3 Ureas

One of the most promising diarylurea (DAU) inhibitors is PQ401, 24, which inhibits the autophosphorylation of IGF-1R in human cultured MCF-7 cells with an IC50 of 12 mM. Treatment of MCNeuA cells implanted into mice with 24 reduced tumor growth when dosed three times per week intraperitoneally [64].

Lead optimization around a series of 3,5-disubstituted 1H-pyr-rolo[2,3-b]pyridines led to the identification of compound 25, which shows potent in vitro kinase activity (IC50 = 21 nM) and inhibits IGF-1R phosphorylation in cells (IC50 = 68 nM) [65].

3.5.4 Pyrrolocarboxaldehydes

Pyrrolocarboxaldehydes have been disclosed as monocyclic ATP-competitive inhibitors of IGF-1R [66]. Aldehyde 26 is modestly selective versus IR in enzymatic and cell-based assays (IGF-1R, IC50 = 490 nM; IR, IC5o = 2 mM) and forms a reversible, covalent adduct with the kinase active site.

3.5.5 Quinolines

IGF-1R inhibitors have also been built around the quinoline core structure. Optimization of the cyanoquinoline template provided 27 with potent IR (IC50 = 2nM) and IGF-1R (IC50 = 9nM) activity as well as activity in a cellular myloid assay with an IC50 of 90 nM [67].

MeO.

MeO.

The isoquinolinedione 28 was identified as an initial micromolar hit that binds at the ATP-binding site in a similar mode to the

benzimidazoles described above (Section 3.5.1). Optimization of R1 and R2 culminated in compound 29 (IGF-1R, IC50 = 319 nM), which is equipotent against IR and has improved selectivity over cyclin-dependent kinase (CDK)-4 [68].

The discovery and development of IGF-1R selective, non ATP-competi-tive inhibitors has been slow relative to ATP-competitive inhibitors due to the inherent medicinal chemistry challenges involved in optimizing potency for the more open substrate-binding site, requiring the use of peptide or peptidomimetic elements. To date, the two main classes of non ATP-competitive inhibitors are catechols and naturally occurring lignans.

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