title: Novel 5- and 6-subtituted benzothiazoles with improved physicochemical properties: potent S1P₁ agonists with in vivo lymphocyte-depleting activity.
abstract: An SAR campaign designed to increase polarity in the 'tail' region of benzothiazole 1 resulted in two series of structurally novel 5-and 6-substituted S1P(1) agonists. Structural optimization for potency ultimately delivered carboxamide (+)-11f, which in addition to possessing improved physicochemical properties relative to starting benzothiazole 1, also displayed good S1P(3) selectivity and acceptable in vivo lymphocyte-depleting activity.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. mfrohn@amgen.com
authors.forename: Mike
authors.initials: M
authors.lastname: Frohn
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Pickrell
authors.forename: Jennifer
authors.initials: J
authors.lastname: Golden
authors.forename: Dalia
authors.initials: D
authors.lastname: Rivenzon-Segal
authors.forename: Scot
authors.initials: S
authors.lastname: Middleton
authors.forename: Mike
authors.initials: M
authors.lastname: Fiorino
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Schrag
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Michele
authors.initials: M
authors.lastname: McElvain
authors.forename: Kristine
authors.initials: K
authors.lastname: Muller
authors.forename: Jerry
authors.initials: J
authors.lastname: Siu
authors.forename: Roland
authors.initials: R
authors.lastname: Bürli
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002627:Chemistry, Physical / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007659:Ketones; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008956:Models, Chemical; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000737:chemistry*
chemical_list: D052160:Benzothiazoles; D007659:Ketones; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D049452:Green Fluorescent Proteins