| Literature DB >> 27726358 |
Hai-Yun Xiao1, Scott H Watterson1, Charles M Langevine1, Anurag S Srivastava1, Soo S Ko1, Yanlei Zhang1, Robert J Cherney1, Wei-Wei Guo1, John L Gilmore1, James E Sheppeck1, Dauh-Rurng Wu1, Peng Li1, Duraisamy Ramasamy2, Piramanayagam Arunachalam2, Arvind Mathur1, Tracy L Taylor1, David J Shuster1, Kim W McIntyre1, Ding-Ren Shen1, Melissa Yarde1, Mary Ellen Cvijic1, Anthony M Marino1, Praveen V Balimane1, Zheng Yang1, Dana M Banas1, Georgia Cornelius1, Celia J D'Arienzo1, Bethanne M Warrack1, Lois Lehman-McKeeman1, Luisa M Salter-Cid1, Jenny Xie1, Joel C Barrish1, Percy H Carter1, Alaric J Dyckman1, T G Murali Dhar1.
Abstract
Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.Entities:
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Year: 2016 PMID： 27726358 DOI： 10.1021/acs.jmedchem.6b01099
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446