Discovery of clinical candidates

More recently, an alternative series of 2-alkoxybenzamides was designed where an intramolecular hydrogen bond mimics the phthalazinone scaffold [19]. Gratifyingly 8 exhibited good PARP inhibition, IC50 = 18 nM. 

PF-01367338 (27) was identified as a clinical chemo- and radio-sensitizer [26] from several series of previously reported bicyclic and tricyclic PARPi. Compounds were evaluated based on their ability to potentiate the activity of TMZ and topotecan in cells, in comparison to control AG14361 (26). Further triage in vivo identified 27 displaying a Ki = 1.4 nM and PF50 = 8.1 in cells. 

A series of indeno[l,2-c]isoquinolines have been described [27] and INO-lOOl has been investigated in the clinic. Although the structure of INO-lOOl has not been reported, sulfonamide 28 is a representative structure (IC50 = lnM, EC5O = 10nM). CEP-9722 is in Phase I clinical trials, while its exact structure has not been disclosed, it is a prodrug of CEP-8983 (29) and patent applications highlight 30. Preclinical efficacy in combination with TMZ and camptothecin have been 

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Figure 1.26. Library-based discovery of clinical candidate C 144-093.

Discovery of clinic candidate pf-4217903-a highly potent and exquisitely selective c-met inhibitor... 

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