Novel S1P(1) Receptor Agonists - Part 1: From Pyrazoles to Thiophenes

作者：Bolli Martin H^*; Mueller Claus; Mathys Boris; Abele Stefan; Birker Magdalena; Bravo Roberto; Bur Daniel; Hess Patrick; Kohl Christopher; Lehmann David; Nayler Oliver; Rey Markus; Meyer Solange; Scherz Michael; Schmidt Gunther; Steiner Beat; Treiber Alexander; Velker Joerg; Weller Thomas

来源：Journal of Medicinal Chemistry, 2013, 56(23): 9737-9755.

DOI：10.1021/jm4014373

From a high-throughput screening campaign aiming at the identification of novel S1P(1) receptor agonists, the pyrazole derivative 2 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 S1P(1) efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound 85 showed EC50 values of 7 and 2880 nM on S1P(1), and S1P(3), 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 S1P(1) selective compound 85 showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only.

• 出版日期2013-12-12