ABSTRACT
FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.
Subject(s)
Drug Discovery , Pyrazoles/administration & dosage , Pyrazoles/pharmacology , Pyridines/administration & dosage , Pyridines/pharmacology , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Cell Line , Dogs , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred Strains , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Sphingosine-1-Phosphate Receptors , Structure-Activity RelationshipABSTRACT
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
