5-Cyanopyrimidine Derivatives as a Novel Class of Potent, Selective, and Orally Active Inhibitors of p38α MAP Kinase

Abstract

A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38alpha.

Structural Comparison of p38 Inhibitor-Protein Complexes: A Review of Recent p38 Inhibitors Having Unique Binding Interactions

“…One of the more recent class of p38 inhibitors that has been disclosed is the substituted benzamide series exemplified by the Bristol-Myers Squibb/Pharmacopeia compound 19 [47] and the Bristol-Myers Squibb compound 20 [48], Fig. (14).…”

“…As predicted, this allows a direct hydrogen bond interaction with the key Met109 residue through the incorporated cyano group. Incorporation of the cyano group as in 20 was demonstrated to improve the p38 enzyme potency relative to the original triazine series by ~ 60 fold [48]. In addition, further substituent optimization to reduce liabilities within the cyanopyrimidine series resulted in: (1) replacement of the N-methyl-N-neopentyl substituent present in 19 with a monosubstituted isopropylamino group in 20 creating an additional hydrogen bond interaction with the Met109 carbonyl, (2) replacement of the N-methoxyamide with an Nisoxazoylamide, and (3) removal of the N-methylhomopiperazine substituent.…”

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…In this system water removal positively amplified the hydrophobic interactions and increased the ligand rigidity leading to a smaller loss in ligand entropy upon binding to the receptor [196]. Another known example of successful water displacement is given by the p38a MAPK, where the displacement of a water molecule by a ligand cyano group yielded a 60-fold improvement in the inhibition constant [227]. As well, the replacement of water by a cyano group resulted in an improvement in ligand binding to scyatolone dehydratase [228].…”

Role of Chemistry in Lead Discovery

“…Initial lead optimization of the triaminotriazines yielded orally active analogs [43] and 5-cyano-4,6-diaminoyrimidines [44] as a novel class of p38 inhibitors. Subsequently, the pyrrolo-[2,1-f] [1,2,4]triazine core, previously identified as a suitable template for kinase inhibitor design [45], was incorporated, and the SAR explored in several small focused libraries led to the discovery and nomination of pyrrolotriazine as a candidate for clinical development [46].…”