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
Optimisation of a series of biaryl sulphonamides resulted in the identification of compound 14 [corrected] which demonstrated dose-dependent and strain-specific inhibition of monocyte recruitment in a thioglycollate-induced peritonitis model of inflammation. [Formula: see text]. [corrected].
Subject(s)
Azoles/chemistry , Receptors, CCR2/antagonists & inhibitors , Sulfonamides/chemistry , Administration, Oral , Animals , Azoles/chemical synthesis , Azoles/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Half-Life , Protein Binding , Rats , Receptors, CCR2/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
The SAR around a V1b antagonist HTS hit 3 was explored to produce a series of thiazole sulfonamides as a lead series with selectivity over the related V1 and oxytocin receptors.
