Synthesis of 4(5)-phenylimidazole-based analogues of sphingosine-1-phosphate and FTY720: discovery of potent S1P1 receptor agonists.
The novel immunosuppressant FTY720 has been demonstrated to elicit immunomodulating effects via interaction with the G-protein coupled receptor S1P(1). FTY720 induced agonism at the S1P(3) receptor, however, has been shown to result in mild bradycardia, a minor side-effect of initial FTY720 therapy. This report describes the synthesis of several potent 4(5)-phenylimidazole-based S1P(1) receptor agonists that are accompanied by poor agonist activity at S1P(3). For instance, compound 20 displayed an EC(50)=4.7+/-1.3 nM at the S1P(1) receptor and EC(50)=780+/-1.3 nM at the S1P(3) receptor using a [gamma-(35)S]GTP-binding assay as compared to phospho-FTY720 (S1P(1): EC(50)=1.3+/-1.3nM, S1P(3): EC(50)=2.0+/-2.4 nM).
Clemens
Jeremy J
JJ
Department of Chemistry, University of Virginia, Charlottesville, VA, USA. clemens@chem.ucla.edu
Davis
Michael D
MD
Lynch
Kevin R
KR
Macdonald
Timothy L
TL
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001919:Bradycardia / Q000188:drug therapy; D016466:CHO Cells; D006224:Cricetinae; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007928:Lethal Dose 50; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000494:pharmacology; D011409:Propylene Glycols / Q000138:chemical synthesis* / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine