Navigating CYP1A Induction and Arylhydrocarbon Receptor Agonism in Drug Discovery. A Case History with S1P₁ Agonists

This article describes the finding of substantial upregulation of mRNA and enzymes of the cytochrome P450 1A family during a lead optimization campaign for small molecule S1P₁ agonists. Fold changes in mRNA up to 10 000-fold for CYP1A1 in vivo in rat and cynomolgus monkey and up to 45-fold for CYP1A1 and CYP1A2 in vitro in rat and human hepatocytes were observed. Challenges observed with correlating induction in vitro and induction in vivo resulted in the implementation of a short, 4 day in vivo screening study in the rat which successfully identified noninducers. Subtle structure–activity relationships in this series of S1P₁ agonists are described extending beyond planarity and lipophilicity, and the impact and considerations of AhR and CYP1A induction in the context of drug development are discussed

Discovery of Tetrahydropyrazolo­pyridine as Sphingosine 1‑Phosphate Receptor 3 (S1P₃)‑Sparing S1P₁ Agonists Active at Low Oral Doses

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

Optimization of Sphingosine-1-phosphate‑1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles

The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P₁ receptors, while a variety of side effects have been ascribed to its S1P₃ receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P₁ receptor agonism. Here we describe a study of the tolerance of the S1P₁ and S1P₃ receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in <i>in vitro</i> and <i>in vivo</i> pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P₁ receptor agonists with good selectivity vs S1P₃ receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development