Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit

Abstract

Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.

Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives

“…The formylation reaction was followed by the Knoevenagel condensation with malonic acid to yield the respective 4-oxo-4H-chromen-3-yl)acrylic acid (20)(21)(22) (Scheme 1). When (E)-ethyl 3-(4-oxo-4H-chromen-3-yl)acrylates (23)(24)(25)(26)(27) were reacted with 1.1 eq. of alkyl amines, then monoalkylated products 28-43 were obtained (Scheme 2).…”

“…Furthermore, 2-pyridone scaffold has been screened against Src kinases. Some 2-pyridone derivatives such as aryl aminoquinazolinepyridone (9) [25], pyrido [2,3-d]pyrimidine (10) [26,27] and pyridopropanamide (11) [28] have been reported as potent Src kinase inhibitors. Thus, the wealth of information for Src kinases and pyridone skeleton obtained from literature provided a strong rationale for considering inhibition of this target using pyridones to treat cancer.…”

Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives

“…1) [26] conserved in its structure; the drug is efficacious in imatinib resistant cases [27]. On the basis of above and considering the literature reports discussing Abl-imatinib structural interactions [16,[26][27][28][29][30][31][32], we decided to conjugate the scaffolds based on 2-pyridone [21,33,34], benzopyran-2-one [35], benzopyran-4-one [22,36], indole acetic acid, iso-nicotinic acid, hippuric acid, piperic acid, 2-oxoquinolinacetic acid, 3-oxobenzooxazinacetic acid [37], and trimethoxyphenyl acrylic acid [38], with PPAP moiety to form the amide/cyclic amide derivatives.…”

Antiviral and Quantitative Structure Activity Relationship Study for Dihydropyridones Derived from Curcumin

“…These compounds are known for their antiproliferative and antitubolin activities (Magedov et al, 2008) and as potential selective inhibitors of receptor tyrosine kinase (Hu et al, 2008;Goodman et al, 2007). Their ability to induce leukaemic cell differentiation has been demonstrated (Pierce et al, 1981).…”