title: Novel S1P(1) receptor agonists--part 2: from bicyclo[3.1.0]hexane-fused thiophenes to isobutyl substituted thiophenes.
abstract: Previously, we reported on the discovery of a novel series of bicyclo[3.1.0]hexane fused thiophene derivatives that serve as potent and selective S1P1 receptor agonists. Here, we discuss our efforts to simplify the bicyclohexane fused thiophene head. In a first step the bicyclohexane moiety could be replaced by a simpler, less rigid cyclohexane ring without compromising the S1P receptor affinity profile of these novel compounds. In a second step, the thiophene head was simplified even further by replacing the cyclohexane ring with an isobutyl group attached either to position 4 or position 5 of the thiophene. These structurally much simpler headgroups again furnished potent and selective S1P1 agonists (e.g., 87), which efficiently and dose dependently reduced the number of circulating lymphocytes upon oral administration to male Wistar rats. For several compounds discussed in this report lymphatic transport is an important route of absorption that may offer opportunities for a tissue targeted approach with minimal plasma exposure.
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.forename: Jörg
authors.initials: J
authors.lastname: Velker
authors.forename: Claus
authors.initials: C
authors.lastname: Müller
authors.forename: Boris
authors.initials: B
authors.lastname: Mathys
authors.forename: Magdalena
authors.initials: M
authors.lastname: Birker
authors.forename: Roberto
authors.initials: R
authors.lastname: Bravo
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: Ruben
authors.initials: R
authors.lastname: de Kanter
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.forename: David
authors.initials: D
authors.lastname: Lehmann
authors.forename: Solange
authors.initials: S
authors.lastname: Meyer
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.forename: Michael
authors.initials: M
authors.lastname: Scherz
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D001643:Bridged Bicyclo Compounds; D049349:Receptors, Lysosphingolipid; D013876:Thiophenes; C046059:bicyclo(3.1.0)hexane