title: Late-stage optimization of a tercyclic class of S1P3-sparing, S1P1 receptor agonists.
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.
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States. Electronic address: joshua.horan@proteostasis.com.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Horan
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kuzmich
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Pingrong
authors.initials: P
authors.lastname: Liu
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Darren
authors.initials: D
authors.lastname: DiSalvo
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: John
authors.initials: J
authors.lastname: Lord
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Can
authors.initials: C
authors.lastname: Mao
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Hopkins
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Harcken
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Raj
authors.initials: R
authors.lastname: Betageri
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hill-Drzewi
authors.affiliation: Inflammation and Immunology, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Lori
authors.initials: L
authors.lastname: Patenaude
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Patel
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Fletcher
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: Terenzzio
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Linehan
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Xia
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Mita
authors.initials: M
authors.lastname: Patel
authors.affiliation: Non-Clinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Debbie
authors.initials: D
authors.lastname: Studwell
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Miller
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Eugene
authors.initials: E
authors.lastname: Hickey
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Dustin
authors.initials: D
authors.lastname: Smith
authors.affiliation: Non-Clinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Kemper
authors.affiliation: Inflammation and Immunology, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Louise K
authors.initials: LK
authors.lastname: Modis
authors.affiliation: Medicinal Chemistry, Exelixis, 210 East Grand Avenue, South San Francisco, CA 94080, United States.
authors.forename: Lynne C
authors.initials: LC
authors.lastname: Bannen
authors.affiliation: Medicinal Chemistry, Exelixis, 210 East Grand Avenue, South San Francisco, CA 94080, United States.
authors.forename: Diva S
authors.initials: DS
authors.lastname: Chan
authors.affiliation: Medicinal Chemistry, Exelixis, 210 East Grand Avenue, South San Francisco, CA 94080, United States.
authors.forename: Morrison B
authors.initials: MB
authors.lastname: Mac
authors.affiliation: Medicinal Chemistry, Exelixis, 210 East Grand Avenue, South San Francisco, CA 94080, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ng
authors.affiliation: Medicinal Chemistry, Exelixis, 210 East Grand Avenue, South San Francisco, CA 94080, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medicinal Chemistry, Exelixis, 210 East Grand Avenue, South San Francisco, CA 94080, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: René M
authors.initials: RM
authors.lastname: Lemieux
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D010069:Oxadiazoles / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D012995:Solubility; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; D013830:Thiadiazoles; D018698:Glutamic Acid
keywords: Autoimmune; S1P1; S1P3; Solubility