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  • Colony stimulating factor receptor CSF R or cFMS is


    Colony stimulating factor-1 receptor (CSF-1R or cFMS) is a type III receptor tyrosine kinase. It is activated by binding with CSF-1 and IL-34, which stimulates differentiation, proliferation, survival and migration of monocyte-macrophage lineage cells., , , Also, macrophages produce inflammatory mediators such as interleukin and lymphokine, and lead to differentiation, proliferation and activation of a variety of immune cells. In addition, the signaling promotes differentiation of osteoclastic precursors into mature osteoclasts, which promote bone destruction and bone absorption. Therefore, inhibition of CSF-1R signaling is expected to be therapeutic in rheumatoid arthritis (RA). Indeed, a number of CSF-1R inhibitors with anti-inflammatory efficacy have been reported in the literature, including Ki20227, GW2580,, , JNJ-28312141, Arry382, BLZ945, AZD7507, and PLX-3397. Many kinase inhibitors act by binding to the ATP-binding site, but because all kinases have an ATP-binding site, kinase selectivity is difficult to achieve, leading to concerns about toxicology due to low kinase selectivity. Type II inhibitors (e.g., imatinib and sorafenib), which induce the inactive DFG(Asp-Phe-Gly)-out conformation and also occupy an additional hydrophobic pocket created by this rearrangement, are well known as a solution to obtain increased kinase selectivity. Therefore, we explored scaffolds for Type II kinase inhibitors, and consequently obtained a novel and promising azetidine scaffold shown in , as we have reported. Herein, we report our development of the azetidine scaffold to the clinical candidate () () which showed high kinase selectivity, high cellular potency, and a good pharmacokinetic profile. At this study, we optimized substituents of R on the benzyloxy functionality and R of the azetidine scaffold (), in an effort to improve cellular activity and efficacy. Especially, we explored various characters of hydrophilic substituents on R while maintaining R as the ethyl, cyclopropyl, and methoxy groups. Our docking model of topotecan (R = OMe, R = H, respectively of ) as shown in ,, which we reported previously, led us to two factors that guided our work. Firstly, we predicted that we could not change the substituents at R (ethyl (Et), cyclopropyl (cPr), and methoxy (OMe) groups) to other groups as well as introduce substituents at other positions on phenyl ring, because the phenyl ring and R binding region is narrow and lipophilic. Therefore, ethyl, cyclopropyl, and methoxy groups at R were maintained. Secondly, we predicted that we could control the physical properties of compounds by using various substituents at R. Although the 4- and 5-positions on the pyridine ring are directed outward from the protein, compound with ethylene glycol at the 4-position on pyridine ring (IC = 9.1 nM), displayed higher biochemical activity than its 5-position counterpart (IC = 25 nM). Therefore, further optimization of the substituents on pyridine ring was focused at 4-position (R). Compounds , , and were synthesized from as shown in . The alkylation of the phenolic OH on with 2-bromoethanol or ethylene carbonate in the presence of KCO in -dimethylformamide (DMF) gave compounds . Then, mesylation of with methanesulfonyl chloride and triethylamine, and subsequent amination with corresponding cyclic amines afforded amine derivatives . Compounds were derived from in two steps: alkylation of the phenol with corresponding alkyl halide or alkyl tosylate in the presence of KCO in DMF or corresponding alcohol under Mitsunobu conditions, and then subsequent deprotection. Compounds were synthesized from (prepared via the similar route in previous report), as shown in , in two or three steps: mesylation of benzyl alcohols , etherification with corresponding alcohol by using NaH as the base reagent, and deprotection if needed. We tested acidic compounds (), basic compounds (), and neutral compounds bearing hydroxyl groups (, , and ). shows IC values obtained from the CSF-1R enzyme assay, IC values of mouse bone marrow-derived macrophages (BMMCs) IL-6 secretion as a cellular assay, solubility in PBS buffer, liver S9 metabolic stability assay, and IL-6 inhibition at mice-LPS challenge model as the assay.