Design, Synthesis, and Anti-inflammatory Properties of Orally Active 4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38α Mitogen-Activated Protein Kinase Inhibitors

Abstract

A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.

Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38α by molecular dynamics simulations and free energy calculations

“…Experimental assays indicate that the configuration of a-Me-benzyl connected with amide is crucial for the binding affinity, the S-configured inhibitor (11j) displayed 80 times more potency than the corresponding R-configured one (11k) [26]. In the current work, the binding mechanisms of the two inhibitors (see Fig.…”

“…ATP binding site is a hydrophobic pocket of p38a formed by residues VAL38, ALA51, HIS107, LEU108, MET109, and LEU167 [23]. In addition, hydrogen bond interactions of inhibitors with GLU71, MET109, ASP168 are extensively adopted in drug design [23][24][25][26].…”

“…4-(Phenylamino)-pyrrolo[2,1-f] [1,2,4]triazines substituted C6 with amide have been discovered as ATP competitive inhibitors of p38a [26]. Experimental assays indicate that the configuration of a-Me-benzyl connected with amide is crucial for the binding affinity, the S-configured inhibitor (11j) displayed 80 times more potency than the corresponding R-configured one (11k) [26].…”

Role of Chemistry in Lead Discovery

“…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]. It is notable that the development candidate, after several rounds of optimization, still contains the aminomethylbenzamide moiety identified in the first HT screen.…”

Synthesis, analgesic, anti-inflammatory and ulcerogenic properties of some novel N'-((1-(substituted amino)methyl)-2-oxoindolin-3-ylidene)-4-(2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)benzohydrazide derivatives

“…Others are considered to have mixed action on COX-1 and -2 (e.g., ibuprofen, naproxen, diclofenac, etodolac, nabumetone, and meloxicam). Other mechanisms that may contribute to NSAID mediated anti-inflammatory activity include the reduction of superoxide radicals, induction of apoptosis, inhibition of adhesion molecule expression, decrease of nitric oxide synthase, decrease of proinflammatory cytokine levels (tumornecrosis factor-α, interleukin-1), modification of lymphocyte activity, and alteration of cellular membrane functions (6). However, long term clinical usages of NSAIDs are associated with significant side effects such as severe gastrointestinal ulceration, bleeding, intolerance and nephrotoxicity (7,8).…”