Synthesis and SAR studies of a novel class of S1P1 receptor antagonists

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 10; pp. 3548 - 3564
• Main Authors: NAKAMURA, Tsuyoshi, YONESU, Kiyoaki, MIZUNO, Yumiko, SUZUKI, Chie, SAKATA, Yuki, TAKUWA, Yoh, NARA, Futoshi, SATOH, Susumu
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 15.05.2007
• Subjects: Animals; Biological and medical sciences; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - pharmacology; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP - metabolism; Humans; Indicators and Reagents; Lysophospholipids - antagonists & inhibitors; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Spectrometry, Mass, Electrospray Ionization; Sphingosine - analogs & derivatives; Sphingosine - antagonists & inhibitors; Structure-Activity Relationship; Sulfonic Acids - chemical synthesis; Sulfonic Acids - pharmacology; Human; edg1 lysophospholipid receptor; Acetylenic compound; Ether; Benzene derivatives; Sodium compound; Selectivity; Structure-activity relationships; In vitro; Organic sulfide; Primary alcohol; Structure activity relation; Organic salt; Sphingosine-1-phosphate; Affinity; Antagonist; Chemical synthesis; SIP receptor; Ethylenic compound
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.02.048

A series of Sodium 4-[(4-butoxyphenyl)thio]-2'-substituted-1,1'-biphenyl-3- sulfonates were identified as functional sphingosine-1-phosphate (S1P) antagonists with selectivity for the S1P(1) receptor subtype starting from chemical lead 2, which was found while screening our in-house compound library. We performed chemical modifications on each regional structure of compound 2, for example, on the three ring compartments, the benzyl substituents, and the long alkyl chain part. The introduction of a biphenyl skeletal structure and the installation of a hydroxyl group onto the terminal carbon in the side-chain region resulted in the potent derivative 35c, which showed >500-fold more potent S1P(1) inhibitory activity than lead compound 2. We report herein the synthesis and structure-activity relationships of structurally novel S1P(1) receptor antagonists.