Design of Potent and Selective 2-Aminobenzimidazole-Based p38α MAP Kinase Inhibitors with Excellent in Vivo Efficacy

Abstract

We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

“…1A). Awareness of potential CYP activity associated with the imidazole central core led to the difluoroaryl substitution at C-2 with other sterically bulky groups such as tert-butyl as found in the candidate (38). The contribution of the 4-fluorophenyl group to enzymatic affinity can be understood by recognizing that it occupies a hydrophobic pocket of the ATP binding site near the gatekeeper Thr106, as seen in the x-ray co-crystal structure (Fig.…”

“…Following an extensive medicinal chemistry effort to identify potent, selective, and orally active inhibitors of p38 MAPK (38,39), a series of trisubstituted imidazole derivatives were synthesized and tested. This effort resulted in the synthesis of LY2228820 and, for the first time, characterization of its crystal structure in complex with p38a MAPK.…”

Correction of nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition

“…This level of p38 MAPK inhibition has previously been shown to prevent somatic nerve conduction velocity deficits in diabetic rats and counteract collagen-induced arthritic changes in nondiabetic rats. 9,13 LY2161793 is an imidazole-based inhibitor that is specific for the a and b isoforms of MAPK. 13 In vitro selectivity studies against a panel of kinases did not reveal any inhibitory action on p38 MAPK gamma, MAPKactivated protein kinase 2, transforming growth factor-b receptor 1, calmodulin-dependent kinase II, cAMP-dependent protein kinase, cyclin E-cyclindependent kinase 2, phosphatidylinositol 3 kinase (PI3K) and vascular endothelial growth factor receptor 2.…”

“…9,13 LY2161793 is an imidazole-based inhibitor that is specific for the a and b isoforms of MAPK. 13 In vitro selectivity studies against a panel of kinases did not reveal any inhibitory action on p38 MAPK gamma, MAPKactivated protein kinase 2, transforming growth factor-b receptor 1, calmodulin-dependent kinase II, cAMP-dependent protein kinase, cyclin E-cyclindependent kinase 2, phosphatidylinositol 3 kinase (PI3K) and vascular endothelial growth factor receptor 2. 13 Notably, there was no direct effect on protein kinase C b, which has been strongly implicated in diabetic vascular complications, including mouse corpus cavernosum dysfunction.…”

Cytotoxic Effects of Some N-Substituted-2-Amino-1H-Benzimidazoles

“…Therefore, the wide spectrum of biological activities (immunotropic, diuretic, anti histaminic, anti-inflammatory, antiviral) associated with the benzimidazolesis of great interest [1][2][3][4][5][6].The availability of the 2-aminobenzimidazole moiety in the structure of many antihelmithic and antiparasitic drugs support further the importance of the benzimidazole ring system in the development of new and better chemotherapeutical agents [7][8][9][10][11]. Nowadays many 2-aminobenzimidazole derivatives, which are known as microtubule inhibitors were evaluated for their anticancer activity and are appropriate as primary substances for the synthesis of novel anticancer drugs.…”