Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic Acid, (3S)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 Kinases

Abstract

Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.

How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors

“…They screened for a bulky anilino group that could provide the optimum dual inhibition, to eventually identify the 1-(3-fluorobenzyl)-1H-indazol-5-amine as a back-pocket binder in compounds (11) and (12) [45]. The subsequent modifications in the region of the solubilizing group led to the development of BMS-599626 (12) with desirable pharmacodynamics and pharmacokinetic profiles that was advanced into clinical trials [46].…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…Part 1 Clinical Trial Outcomes can lead to dacomitinib resistance [177]. BMS599626 (AC480) is also a second-generation pan-HER inhibitor [178,179] that appears to be a radiosensitizing agent [179]. Somewhat surprisingly, the dose-limiting toxicities were not the usual mucocutaneous toxicities, which did occur, but rather QT prolongation and elevation of liver transaminases with a maximum-tolerated dose of 600 mg daily [180].…”

5,6-Dimethyl-1,2,4-triazin-3-amine

“…For the biological and medical applications of triazine, see: Anderson et al(2003); Gavai et al (2009); Hunt et al (2004). For the structures of complexes containing triazine, see: Drew et al (2001); Li et al (2009); Machura et al (2008).…”

“…The heterocyclic nitrogen compounds containing 1,2,4-triazine moieties have drawn much attention in recent years, owing to their interesting biological and medicinal properties (Anderson et al, 2003;Gavai et al, 2009;Hunt et al,2004). They usually act as efficient ligands in supramolecular compounds (Drew et al, 2001;Li et al, 2009;Machura et al, 2008).…”