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 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 S1P1 efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound 85 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 85 showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only.

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…Both S1PR1 and S1PR3 are expressed in the heart (Mazurais et al, 2002). Some studies suggested that S1PR3, and not S1PR1, mediates transient bradycardia in response to S1P (Forrest et al, 2004) and nonselective S1PR agonists (Forrest et al, 2004;Sanna et al, 2004); however, recent studies demonstrated that S1PR1 can also contribute to the bradycardia upon treatment with FTY720 (Murakami et al, 2010), with BAF312, a S1PR1,5 selective agonist (Fryer et al, 2012), and other S1PR1 agonists (Hamada et al, 2010;Bolli et al, 2013).…”

Trifluoromethylation of aryl and heteroaryl halides

“…65b In their quest for novel thiophene derivatives as immunosuppressive agents, Bolli and colleagues reported a relatively large scale (w18 g) trifluoromethylation of 3-iodo-N-methoxy-N,5,5-trimethyl-4,5,6,7-tetrahydrobenzo [c]thiophene-1-carboxamide with methyl chlorodifluoroacetate (2.4 equiv), CuI (1.6 equiv), and KF (1.6 equiv) in DMF at 134 C (Scheme 19). 66 Here, ClCF 2 CO 2 Me was added at 134 C over a period of 4 h to keep it at a low concentration and the corresponding trifluoromethyl product was obtained in 91% yield. The product was then converted to the targeted compound.…”

Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters

“…Because of its special structure and bioactive activities, screening of structurally modified 3-carene derivatives for their bioactivity has received considerable attention. For instance, stable, potent, and selective sphingosine-1-phosphate receptor 1 (S1P 1 ) agonists were successively synthesized by using (+)-3-carene as starting material [ 11 ]. Ingenol and (+)-phorbol, two crucial natural products with various biological activities, especially anticancer, have been also synthesized from inexpensive (+)-3-carene [ 12 , 13 , 14 , 15 ].…”