title: Novel S1P1 receptor agonists--part 1: From pyrazoles to thiophenes.
abstract: From a high-throughput screening campaign aiming at the identification of novel S1P1 receptor agonists, the pyrazole derivative 2 emerged as a hit structure. Medicinal chemistry efforts focused not only on improving the potency of the compound but in particular also on resolving its inherent instability issue. This led to the discovery of novel bicyclo[3.1.0]hexane fused thiophene derivatives. Compounds with high affinity and selectivity for S1P1 efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound 85 showed EC50 values of 7 and 2880 nM on S1P1 and S1P3, respectively, had favorable pharmacokinetic properties in rat and dog, distributed well into brain tissue, and efficiently and dose dependently reduced the blood lymphocyte count in the rat. After oral administration to spontaneously hypertensive rats, the S1P1 selective compound 85 showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only.
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, Allschwil CH-4123, Switzerland.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.forename: Claus
authors.initials: C
authors.lastname: Müller
authors.forename: Boris
authors.initials: B
authors.lastname: Mathys
authors.forename: Stefan
authors.initials: S
authors.lastname: Abele
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: 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: Oliver
authors.initials: O
authors.lastname: Nayler
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.forename: Solange
authors.initials: S
authors.lastname: Meyer
authors.forename: Michael
authors.initials: M
authors.lastname: Scherz
authors.forename: Gunther
authors.initials: G
authors.lastname: Schmidt
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Jörg
authors.initials: J
authors.lastname: Velker
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
mesh_terms: D000818:Animals; D004285:Dogs; D004355:Drug Stability; D018655:Lymphocyte Count; D008246:Lysophospholipids / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D008246:Lysophospholipids; D011720:Pyrazoles; D049349:Receptors, Lysosphingolipid; D013876:Thiophenes; C060506:sphingosine 1-phosphate; D013110:Sphingosine