title: Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.
abstract: We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.
authors: Medicinal Chemistry, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. lewpenn@me.com
authors: Lewis D
authors: LD
authors: Pennington
authors: Michael D
authors: MD
authors: Croghan
authors: Kelvin K C
authors: KK
authors: Sham
authors: Alexander J
authors: AJ
authors: Pickrell
authors: Paul E
authors: PE
authors: Harrington
authors: Michael J
authors: MJ
authors: Frohn
authors: Brian A
authors: BA
authors: Lanman
authors: Anthony B
authors: AB
authors: Reed
authors: Matthew R
authors: MR
authors: Lee
authors: Han
authors: H
authors: Xu
authors: Michele
authors: M
authors: McElvain
authors: Yang
authors: Y
authors: Xu
authors: Xuxia
authors: X
authors: Zhang
authors: Michael
authors: M
authors: Fiorino
authors: Michelle
authors: M
authors: Horner
authors: Henry G
authors: HG
authors: Morrison
authors: Heather A
authors: HA
authors: Arnett
authors: Christopher
authors: C
authors: Fotsch
authors: Andrew S
authors: AS
authors: Tasker
authors: Min
authors: M
authors: Wong
authors: Victor J
authors: VJ
authors: Cee
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002318:Cardiovascular Diseases / Q000378:metabolism; D002627:Chemistry, Physical / Q000379:methods*; D015195:Drug Design; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008956:Models, Chemical; D009103:Multiple Sclerosis / Q000188:drug therapy; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D007166:Immunosuppressive Agents; D015363:Quinolones; D049349:Receptors, Lysosphingolipid