Synthesis, Structure−Activity Relationship and in Vivo Antiinflammatory Efficacy of Substituted Dipiperidines as CCR2 Antagonists

Abstract

A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.

Pharmacological Profile of JNJ-27141491 [(S)-3-[3,4-Difluorophenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl Acid Methyl Ester], as a Noncompetitive and Orally Active Antagonist of the Human Chemokine Receptor CCR2

“…JNJ-27141491 was synthesized at the Department of Medicinal Chemistry at Johnson & Johnson Pharmaceutical Research and Development (Beerse, Belgium) according to the methods described by Doyon et al (2008). Reference compounds were synthesized as described previously: INCB3344 (Brodmerkel et al, 2005), compound 7a (Xia et al, 2007), and UCB-102405 (Dasse et al, 2007). For in vitro experiments, compounds were dissolved at 5 mM in dimethyl sulfoxide (DMSO) and appropriately diluted in the indicated buffers, with a final DMSO concentration of 1% in […”

“…2, B-D). For comparison, in the MCP-1-induced Ca 2ϩ mobilization assay in THP-1 cells, the known experimental CCR2 antagonists INCB3344 (Brodmerkel et al, 2005), compound 7a (Xia et al, 2007), and UCB-102405 suppressed the reaction, with IC 50 values of 13, 13, and 0.8 nM, respectively. JNJ-27141491 also inhibited chemotaxis of human PBMC toward MCP-1, with an IC 50 value of 97 Ϯ 16 nM (Fig.…”

“…Moreover, genetic deletion of either CCR2 or MCP-1 showed a selective defect in migration of macrophages to sites of inflammation (Kurihara et al, 1997;Lu et al, 1998) and protection in inflammatory disease models such as experimental autoimmune encephalomyelitis (EAE) (Fife et al, 2000;Izikson et al, 2000;Huang et al, 2001) and atherosclerosis (Boring et al, 1998;Gosling et al, 1999). Furthermore, a reduction of disease in models of arthritis, MS, and asthma was demonstrated after treatment with anti-MCP-1 antibodies (Ogata et al, 1997;Kennedy et al, 1998), an anti-CCR2 antibody (Mellado et al, 2008), or low-molecular weight CCR2 antagonists (Brodmerkel et al, 2005;Higgins et al, 2007;Xia et al, 2007). These observations led to the hypothesis that CCR2 could represent a potentially attractive disease target.…”

Qsar in-Silico Method Analysis of Antitumoral Acridones as a Anticancerous Agent and Dipiperidines as Ccr2 Antagonists

“…[4] The 2D QSAR models were prformed using simple regression and multiple regression method. The 3D QSAR was performed by using chem.…”

“…For the present QSAR study, two series was selected, Series 1-Tricyclic quinolones as antitumoral acridones which was having the cytotoxic activity against both HL-60 and P388 leukemias and a wide panel of human and rodent solid tumor cells and Series 2-Dipiperidines as CCR2 antagonist. [3][4] Quantitative structure activity relationship (QSAR) searches information relating chemical structure to biological and other activities by developing a QSAR model. Using such an approach one could predict the activities of newly designed compounds before a decision is being made whether these compounds should be really synthesized and tested.…”