Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate.

Abstract

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

• Authors: Emmanuel H Demont, Benjamin I Andrews, Rino A Bit, Colin A Campbell, Jason W B Cooke, Nigel Deeks, Sapna Desai, Simon J Dowell, Pam Gaskin, James R J Gray, Andrea Haynes, Duncan S Holmes, Umesh Kumar, Mary A Morse, Greg J Osborne, Terry Panchal, Bela Patel, Alcide Perboni, Simon Taylor, Robert Watson, Jason Witherington, Robert Willis
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 2 Issue 6 Pg. 444-9 (Jun 09 2011) ISSN: 1948-5875 [Print] United States
• PMID: 24900328 (Publication Type: Journal Article)