학술논문
Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3 )-Sparing S1P1 Agonists Active at Low Oral Doses.
Document Type
Article
Author
Demont, Emmanuel H.; Bailey, James M.; Bit, Rino A.; Brown, Jack A.; Campbell, Colin A.; Deeks, Nigel; Dowell, Simon J.; Eldred, Colin; Gaskin, Pam; Gray, James R. J.; Haynes, Andrea; Hirst, David J.; Holmes, Duncan S.; Kumar, Umesh; Morse, Mary A.; Osborne, Greg J.; Renaux, Jessica F.; Seal, Gail A. L.; Smethurst, Chris A.; Taylor, Simon
Source
Subject
*PYRIDINE
*SPHINGOSINE-1-phosphate
*MULTIPLE sclerosis treatment
*DRUG development
*DRUG dosage
*ORAL drug administration
*THERAPEUTICS
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Language
ISSN
0022-2623
Abstract
FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines. [ABSTRACT FROM AUTHOR]