2. Academic Validation
  3. Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists

Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists

  • Bioorg Med Chem Lett. 2016 Jan 15;26(2):466-471. doi: 10.1016/j.bmcl.2015.11.090.
Joshua C Horan 1,  Daniel Kuzmich 2,  Pingrong Liu 2,  Darren DiSalvo 2,  John Lord 2,  Can Mao 2,  Tamara D Hopkins 2,  Hui Yu 2,  Christian Harcken 2,  Raj Betageri 2,  Melissa Hill-Drzewi 2,  Lori Patenaude 3,  Monica Patel 2,  Kimberly Fletcher 2,  Donna Terenzzio 2,  Brian Linehan 2,  Heather Xia 2,  Mita Patel 2,  Debbie Studwell 4,  Craig Miller 2,  Eugene Hickey 2,  Jeremy I Levin 2,  Dustin Smith 2,  Raymond A Kemper 4,  Louise K Modis 3,  Lynne C Bannen 5,  Diva S Chan 5,  Morrison B Mac 5,  Stephanie Ng 5,  Yong Wang 5,  Wei Xu 5,  René M Lemieux 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States. Electronic address: joshua.horan@proteostasis.com.
  • 2 Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
  • 3 Inflammation and Immunology, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
  • 4 Non-Clinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
  • 5 Medicinal Chemistry, Exelixis, 210 East Grand Avenue, South San Francisco, CA 94080, United States.
PMID: 26687487 DOI: 10.1016/j.bmcl.2015.11.090
Abstract

Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.

Keywords

Autoimmune; S1P1; S1P3; Solubility.

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