Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

Abstract

b S Supporting Information M acrophages, which are derived from monocytes, a subset of leukocytes, are well-characterized mediators of tissue destruction. These cells can be activated to secrete proinflammatory cytokines such as TNFR and IL-1β, tissue-degrading enzymes such as MMPs, and other chemokines that mediate the influx of other inflammatory cells. 1 Excessive recruitment of these cells to sites of inflammation leads to significant tissue destruction and contributes to the morbidity of chronic inflammatory and autoimmune diseases. The trafficking of monocytes/ macrophages to sites of inflammation is believed to be predominantly mediated by monocyte chemoattractant protein-1 (MCP-1, CCL2) through interaction with its specific receptor, CCR2, which is a member of the super family of seven-transmembrane G-protein-coupled receptors (GPCRs) and is predominantly expressed on monocytes. Binding of MCP-1 to CCR2 induces chemotaxis, resulting in directed migration of monocytes/macrophages to disease sites where MCP-1 expression is elevated. 2 Studies in rodent models have demonstrated the critical role of MCP-1/CCR2 in inflammatory and autoimmune diseases and strongly suggest that CCR2 is an attractive therapeutic target. 3 As a result, inhibition of CCR2 has emerged as a novel therapeutic approach for pharmaceutical research, and a number of potent small molecule CCR2 antagonists have been identified. 4À10 We have reported the discovery of a novel series of CCR2 antagonists through rational design. 10 Our structureÀactivity relationship (SAR) studies on that series of compounds led to the identification of INCB3344 (Figure 1), a potent, selective, and orally bioavailable antagonist of human and murine CCR2 (hCCR2 and mCCR2). INCB3344 has been used as a tool compound for target validation in rodent models because of its potent inhibitory activity toward murine CCR2, its selectivity over other homologous chemokine receptors, and its good pharmacokinetics profile but was not suitable as a clinical candidate due to its moderate hERG activity (IC 50 = 13 μM) as assessed using a dofetilide binding assay, which did not meet our criteria in hERG binding activity. In addition, INCB3344 was an inhibitor of CYP3A4.In the course of SAR studies on the INCB3344 series in an attempt to identify a clinical candidate, we discovered that removal of the ethoxy at the 3-position on the pyrrolidine in the INCB3344 series as in 1 (Figure 2) resulted in a significant loss in mCCR2 activity but retained the hCCR2 activity as in 2 (Figure 2). An R configuration at the 3-position on the pyrrolidine as shown in 2 is required for activity as the S enantiomer of 2 displayed an IC 50 of >1 μM in hCCR2 MCP-1 assay. Although this des-ethoxy series is not superior to the INCB3344 series by comparison of 2 with 1 in hCCR2 activity and hERG binding activity, the 1,3-disubstituted pyrrolidine core in this series offers an advantage over the 1,3,4-trisubstituted pyrrolidine core in the INCB3344 series from a synthetic point of view as the former ...

The chemokine fragment CXCL9(74–103) diminishes neutrophil recruitment and joint inflammation in antigen-induced arthritis

“…43,44 Consequently, targeting chemokines with inhibitors, antibodies, and antagonists as new options in the treatment of patients with arthritis was promising. The development of antagonists of CCR1, 44,45 CCR2, 46,47 and CCR5 48 presented promising results in different murine models of arthritis, but the antagonists failed during clinical trials. Many reasons can be found to explain the failure in the development of these drugs, such as inappropriate target selection in some cases, insufficient dosing of chemokine receptor antagonists in vivo, 49 and problems related to properties and complexity of the chemokine system, including redundancy and pleiotropy.…”

International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

“…The CCR2 antagonist failed to show any significant improvement compared with placebo for any of the end points studied (Horuk, 2009). Incyte (Wilmington, DE) has disclosed a number of CCR2 antagonists, including INCB3284, which was one of their clinical compounds in phase II clinical studies for multiple sclerosis and lupus (Xue et al, 2011). No data from the clinical trials were ever reported.…”

HIV-1 Infection: The Functional Importance of SDF1, CCR2 and CCR5 in Protection and Therapeutics

“…Although the structure of these antagonist is different from each other but still all of them share the same binding pocket onto CCR5 receptor with differential binding mode [28]. INCB 3284 dimesylate, BMS CCR2 22, JNJ 27141491, RS 504393, Teijin compound 1, RS 102895 hydrochloride, are selective CCR2 antagonist (Figure 1), where INCB 3284 dimesylate and JNJ 27141491 are orally bio available for their potency [29][30][31][32][33]. Gamma amino butyric acid (Table 1) is a potent inhibitor for SDF1 and it is explored well for its efficacy for inhibition of migration of CD133+ haematopoietic stem cells and progenitor cells but the same will be effective for HIV1 treatment or not is not explored well.…”