The utility of pharmacokinetic-pharmacodynamic modeling in the discovery and optimization of selective S1P(1) agonists.
Xenobiotica
; 42(7): 671-86, 2012 Jul.
Article
in En
| MEDLINE
| ID: mdl-22225501
ABSTRACT
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 ß arrestin recruitment and G-protein signalling. A structurally novel S1P(1) agonist was identified and predictions of human pharmacokinetics and clinical dose are presented.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Propylene Glycols
/
Sphingosine
/
Lysophospholipids
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Xenobiotica
Year:
2012
Document type:
Article
Affiliation country:
United kingdom