Novel S1P₁ Receptor Agonists – Part 1: From Pyrazoles to Thiophenes

Abstract

From a high-throughput screening campaign aiming at the identification of novel S1P₁ receptor agonists, the pyrazole derivative <b>2</b> emerged as a hit structure. Medicinal chemistry efforts focused not only on improving the potency of the compound but in particular also on resolving its inherent instability issue. This led to the discovery of novel bicyclo[3.1.0]­hexane fused thiophene derivatives. Compounds with high affinity and selectivity for S1P₁ efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound <b>85</b> showed EC₅₀ values of 7 and 2880 nM on S1P₁ and S1P₃, respectively, had favorable pharmacokinetic properties in rat and dog, distributed well into brain tissue, and efficiently and dose dependently reduced the blood lymphocyte count in the rat. After oral administration to spontaneously hypertensive rats, the S1P₁ selective compound <b>85</b> showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only