RWJ-540973

Me 1-(2-chloroacetyl)-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate was synthesized by the condensation of 3-carboxymethyl-2,6-diphenylpiperidine-4-one with chloroacetylchloride, and characterized by FT-IR spectroscopy.The study revealed that the piperidine ring adopts boat conformation with equatorial orientation of two Ph rings at C-2 and C-6.Intermol. contacts and hydrogen bonding interactions were explored by Hirshfeld surface and 2D fingerprint analyses, showing that the major contact were H···H (57.7%), C···H/H···C (14.2%), O···;H/H···O (15.3), Cl···H/H···Cl (7.1%) and C···Cl/Cl···C (12.7%).Intramol. interaction was examined through the Radiant d. gradient (RDG), Interaction region indicator (IRI), Electron localization function (ELF), and localized orbital locator (LOL) to understand hyperconjugation and ·-electrons delocalization in the mol.DFT studies such as structure optimization, HOMO-LUMO orbital anal. and mol. electrostatic potential were conducted for the title compoundThe topol. of the mol. arrangement and intermol. interaction energies were determined through 3D energy framework anal.Subsequently, the Me 1-(2-chloroacetyl)-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate was subjected to ADMET anal. to extend its scope of bioavailability.Mol. docking studies were then employed using the tyrosine kinase inhibitor, epidermal growth factor receptor (EGFR) enzymes (PDB ID: 4WKQ and 6JOL).The study revealed significant interactions between the title ligand structure and active sites of selected proteins complex.

Increased invasion of synovial fibroblasts and their involvement in cartilage damage are characteristic phenotypes of rheumatoid arthritis (RA). To identify low molecular weight compounds that suppress synovial fibroblast invasion, a panel of inhibitors (n = 330) was initially screened using a real-time cell analysis system for human synovial fibroblasts that were enzymatically isolated from surgical samples of RA patients. To evaluate the effects of the inhibitors identified in the screen, synovial fibroblast migration was measured using a wound-healing assay, and phosphorylation of intracellular signaling molecules was determined by immunoblots. Several candidate inhibitors were identified in the screen, including inhibitors against platelet-derived growth factor receptor (PDGFR), Akt, PI3K, and glycogen kinase synthetase 3 (GSK-3). These inhibitors strongly suppressed synovial fibroblast migration after 72 h and downregulated phosphorylation of Akt (Ser473) at 48 h. When the inhibitors were removed from the culture conditions, both migration and phosphorylated Akt (Ser473) levels were restored. Furthermore, all the categories of inhibitors except for PDGFR inhibitor IV decreased cell proliferation as well as IL-6 production in synovial fibroblasts. Interestingly, GSK-3 inhibitors increased anti-inflammatory cytokine IL-10 production but suppressed IL-23 production from LPS-primed macrophages obtained from healthy donors. In conclusion, blocking PDGFR, PI3K, or GSK-3 could have therapeutic value as an RA treatment that targets the invasion/migration of synovial fibroblasts.