Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists.
Bioorg Med Chem Lett
; 20(8): 2520-4, 2010 Apr 15.
Article
em En
| MEDLINE
| ID: mdl-20304639
ABSTRACT
In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de Lisoesfingolipídeo
/
Amino Álcoois
Limite:
Animals
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article