title: Piperazinyl-oxadiazoles as selective sphingosine-1-phosphate receptor agonists.
abstract: The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States. Electronic address: josh.horan@boehringer-ingelheim.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: Sulagna
authors.initials: S
authors.lastname: Sanyal
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Younggi
authors.initials: Y
authors.lastname: Choi
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: Patnaude
authors.affiliation: Inflammation and Immunology, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Inflammation and Immunology, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Fogal
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: Brian N
authors.initials: BN
authors.lastname: Cook
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gueneva-Boucheva
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fisher
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: Edward
authors.initials: E
authors.lastname: Pack
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 M
authors.initials: SM
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: 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, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, United States.
authors.forename: René M
authors.initials: RM
authors.lastname: Lemieux
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D008231:Lymphopenia / Q000139:chemically induced / Q000473:pathology; D015394:Molecular Structure; D010069:Oxadiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship
chemical_list: D010069:Oxadiazoles; D010879:Piperazines; D049349:Receptors, Lysosphingolipid; C578616:S1PR1 protein, rat; D000081025:Sphingosine-1-Phosphate Receptors; C000596293:piperazine-1,2,4-oxadiazole
keywords: Agonist; Lymphopenia; Prodrug; S1P1; S1P3