Synthesis and Structure−Activity Relationship of Aminobenzophenones. A Novel Class of p38 MAP Kinase Inhibitors with High Antiinflammatory Activity

Abstract

We wish to report the synthesis and structure-activity relationship (SAR) of a series of 4-aminobenzophenones, as a novel compound class with high antiinflammatory activity. Our initial lead, (4-[(2-aminophenyl)amino]phenyl)(phenyl)methanone (3), was systematically optimized and resulted in compounds that potently inhibited the release of the proinflammatory cytokines IL-1beta and TNF-alpha in human peripheral blood mononuclear cells stimulated by LPS. One of the most potent compounds, among others, was (4-[(2-aminophenyl)amino]-2-chlorophenyl)(2-methylphenyl)methanone (45) with IC(50) values of 14 and 6 nM for the inhibition of IL-1beta and TNF-alpha, respectively. Furthermore, we found these types of compounds to be potent and selective p38 MAP kinase inhibitors, e.g. 45 had an IC(50) value of 10 nM. Molecular modeling was used to rationalize our SAR data and to propose a model for the interaction of compound 45 with the p38 MAP kinase. The model involved a favorable hydrogen bond between the carbonyl group of the benzophenone and the NH of Met-109, positioning ring A in the hydrophobic pocket I of the enzyme. Good antiinflammatory effects were demonstrated in two murine models of dermatitis after topical application (oxazolone and TPA model).

Redetermination of the structure of N-(2-benzoyl-4-chlorophenyl)-2- chloroacetamide, C15H11Cl2NO2

“…Benzophenone and related compounds have been reported to show antiallergic, antiinflammatory, antiasthmatic, antimalarial, anti-microbial and antianaphylactic activity [1]. 4-Aminobenzophenones have high anti-inflammatory activity [2], a benzophenyl cyano derivative acts as a vasorelaxant [3] and the piperidinyl derivative produces analgesia [4]. Certain aminothiophenes of phenylmethanone are positive allosteric regulators of the human A1 adenosine receptor [5] and biphenyl derivatives show moderate to high activity against Mycobacterium tuberculosis in in vitro studies [6].…”

Synthesis and biological evaluation of N-cyclopropylbenzamide-benzophenone hybrids as novel and selective p38 mitogen activated protein kinase (MAPK) inhibitors

“…4 Further investigation into the binding mode of 4-aminobenzophenones within p38a MAPK active site by Laufer and his co-workers 5 disclosed that oxygen of carbonyl moiety in these derivatives makes a tight interaction with a hinge region of the kinase by forming strong double hydrogen bondings with the NH-group of Met109 and another NH-group of Gly110 instead of amide oxygen via glycine flip (PDB ID: 3QUD). 2a,6 This interaction provides high selectivity to the inhibitor toward p38a MAPK because it is only possible when the kinase has a hinge region composed of glycine and adjacent linker residue such as methionine, which exists in 9.2% of all kinases.…”

Synthesis and Anti‐Inflammatory Activity of Novel (4‐Hydroxyphenyl)(2,4‐dimethoxyphenyl) Methanone Derivatives

“…Benzophenone analogues synthesized by several scientists have been reported as effective anti-inflammatory agents [4 -6]. Recently, the synthesis and structure-activity relationship of benzophenones as a novel class of p38-MAP kinase inhibitors with high anti-inflammatory activity have been reported [7]. We are interested to incorpo-rate a piperidine group in one of the phenyl rings, since the piperidine scaffold is wide-ranging in its therapeutic uses as it is ubiquitously found in drugs.…”