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Bioorg Med Chem Lett. 2016 Jan 15;26(2):466-471. doi: 10.1016/j.bmcl.2015.11.090. Epub 2015 Nov 26.

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

Author information

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.

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

PMID:
26687487
DOI:
10.1016/j.bmcl.2015.11.090
[Indexed for MEDLINE]

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