The utility of pharmacokinetic-pharmacodynamic modeling in the discovery and optimization of selective S1P(1) agonists.
Sphingosine-1-phosphate (S1P(1)) receptor agonists such as Fingolimod (FTY-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. This class of compound act by inducing peripheral lymphopenia. Using an integrated pharmacokinetic/pharmacodynamic (PK-PD) approach based on an in vivo rat model, novel S1P(1) agonists were identified with a predicted more rapid rate of reversibility of lymphocyte reduction in human compared to Fingolimod. The in vivo potency of 15 compounds based on PK-PD modelling of the rat lymphocyte reduction model was correlated with in vitro measures of potency at the S1P(1) receptor using β arrestin recruitment and G-protein signalling. A structurally novel S1P(1) agonist was identified and predictions of human pharmacokinetics and clinical dose are presented.
Immuno-Inflammation Center of Excellence for Drug Discovery , GlaxoSmithKline, Stevenage, UK. Simon.5.taylor@gsk.com
Simon
S
Taylor
James R J
JR
Gray
Robert
R
Willis
Nigel
N
Deeks
Andrea
A
Haynes
Colin
C
Campbell
Pam
P
Gaskin
Karen
K
Leavens
Emmanuel
E
Demont
Simon
S
Dowell
Jenni
J
Cryan
Mary
M
Morse
Aarti
A
Patel
Helen
H
Garden
Jason
J
Witherington
D000818:Animals; D019393:Arrestin / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D019204:GTP-Binding Proteins / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000819:agonists* / Q000378:metabolism; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy; D011409:Propylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D019393:Arrestin; D008246:Lysophospholipids; D011409:Propylene Glycols; C060506:sphingosine 1-phosphate; D019204:GTP-Binding Proteins; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine