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    • Carmustine However cancer and fibrotic diseases are the most

    2023-01-30

    However, cancer and fibrotic diseases are the most extensively studied disease states. ATX is connected to various cancers because it can stimulate chemokinesis and chemotaxis in melanoma cells. Upregulated ATX Carmustine has been reported in breast cancer,, prostate cancer, thyroid cancer, non-small-cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, ovarian cancer and Hodgkin’s lymphoma. Furthermore, ATX-LPA signaling pathway is involved in numerous chronic fibrotic diseases which are associated with kidney, liver, synovial joints, lung, retina, and adipose tissues. ATX is considered as a potential target for therapeutic intervention. The discovery and development of novel chemical compounds which are capable of modulating the ATX-LPA pathway has become an active area of research in pharmaceutical science. At present, no ATX inhibitor has been approved for the treatment. However, several small molecule ATX inhibitors have been reported by pharmaceutical companies as well as academic communities. This includes PF-8380 (IC=2.80nM, FS-3 and IC=1.70, LPC), HA155 (IC=5.70nM, LPC), PAT-347 (IC=2.00nM, LPC) and GLPG1690 (IC=131.00nM, LPC and IC=242.00nM, human plasma assay). To date, GLPG1690 is the only one ATX inhibitor that has progressed to clinical trials for the treatment of idiopathic pulmonary fibrosis (IPF). Compounds containing 4-phenyl-thiazole core have been probed for different biological activities such as anticancer, antifungal and antiviral agents., GLPG1690 () also contains 4-phenyl-thiazole moiety. In the present work, we intended to investigate this moiety synthesis and evaluation of a series of 4-phenyl-thiazole analogues. Herein, we report the design, synthesis, structure-activity relationship (SAR), docking and biological evaluation of the 4-phenyl-thiazole based ATX inhibitors. Development strategy of the synthesized compounds is presented in . We have designed twenty-five compounds and evaluated their inhibitory activity on ATX using FS-3 and human plasma assays. A systematic SAR analysis was performed to define relationship between chemical structures and their inhibitory activities. Binding mode of the series was proposed through molecular docking studies. The synthesis of compounds is outlined in , , , . The synthesized compounds were evaluated for their activity against ATX using FS-3 assay. The structures and IC values of the tested compounds are provided in . It is obvious from that compounds , and showed high activities (IC=4.47, 2.99 and 2.19nM, respectively). Furthermore, compounds , , , and displayed moderate activities (75.90, 10.30, 13.67, 63.29 and 30.25nM, respectively). The remaining compounds showed relatively low ATX inhibitory activities (>100nM). Using FS-3 assay results, we attempted to define SAR around this chemotype in order to improve the understanding about the structural features which contribute to its potency. Initially, we synthesized several compounds with different R groups to obtain a compound with high inhibitory activity. Most of the substitutions couldn’t produce satisfactory activity. However, Compound with 4-amino-piperidine-1-carboxylic acid benzyl ester moiety at R position exhibited IC value of 1301.00nM. Compound with 3-amino-pyrrolidine-1-carboxylic acid benzyl ester moiety at R position displayed IC value of 1233.00nM. Furthermore, Compound with 4-formylamino-piperidine-1-carboxylic acid benzyl ester moiety at R position showed reasonable activity (IC=504.50nM) and compound with 4-formylamino-piperidine-1-carboxylic acid 3,5-dichloro-benzyl ester moiety at R position displayed high potency (IC=4.47nM). We modified R and R groups of the selected compounds (, , , and ) in order to improve the activity. Different substituents on couldn’t produce reasonable ATX inhibitory activity. Interestingly, modification of R and R groups on , , and produced compounds with promising inhibitory activities. Substitution of methylphosphonic acid group at R position in compounds (IC=10.30nM), (IC=75.90nM), (IC=13.67nM) and (IC=2.19nM) showed drastic improvement in the activity. In addition, with chloro group and with methoxy substituent at R position exhibited IC values of 63.29 and 30.25nM, respectively. with methanesulfonamide group at R position displayed IC value of 2.99nM. Compound with IC value of 2.19nM was found to be most potent compound of the series. Additionally, compound exhibited better inhibitory potency than PF-8380, which is reported to have IC value of 2.80nM in the FS-3 assay.