2. Academic Validation
  3. Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists

Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists

  • J Med Chem. 2012 Feb 9;55(3):1368-81. doi: 10.1021/jm201533b.
Mohamed A Ibrahim 1,  Henry W B Johnson,  Joon Won Jeong,  Gary L Lewis,  Xian Shi,  Robin T Noguchi,  Matthew Williams,  James W Leahy,  John M Nuss,  John Woolfrey,  Monica Banica,  Frauke Bentzien,  Yu-Chien Chou,  Anna Gibson,  Nathan Heald,  Peter Lamb,  Larry Mattheakis,  David Matthews,  Aaron Shipway,  Xiang Wu,  Wentao Zhang,  Sihong Zhou,  Geetha Shankar
Affiliations

Affiliation

  • 1 Department of Drug Discovery, Exelixis, 169 Harbor Way, South San Francisco, California 94083, United States.
PMID: 22214363 DOI: 10.1021/jm201533b
Abstract

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.

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