Pharmacophore-Based Design of Sphingosine 1-phosphate-3 Receptor Antagonists That Include a 3,4-Dialkoxybenzophenone Scaffold

Abstract

Sphingosine 1-phosphate (S1P) receptors are G-protein-coupled receptors. Among the five identified subtypes S1P1-5, the S1P3 receptor expressed on vascular endothelial cells has been shown to play an important role in cell proliferation, migration, and inflammation. A pharmacophore-based database search was used to identify a potent scaffold for an S1P3 receptor antagonist by common feature-based alignment and further validated using the Güner-Henry (GH) scoring method. Assumed excluded volumes were merged into this model to evaluate the steric effect with the S1P3 receptor. Three commercially available compounds were identified as S1P3 receptor antagonists, with IC50 values <5 microM. The synthesis of further derivatives revealed that the 3,4-dialkoxybenzophenone scaffold is a potent component of an S1P3 receptor antagonist. Our results indicate that pharmacophore-based design of S1P3 receptor antagonists can be used to expand the possibility of structural modification through scaffold-hopping based on a database search.

Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

“…Finally, 3a-P is 1 log order more potent than previously reported S1P 3 antagonists. 25 However, we do not know at present whether antagonism at the S1P 3 receptor would have any therapeutic benefit.…”

International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature: TABLE 1

“…The (R)-3-amino-(3-hexylphenylamino)-4-oxobutylphosphonic acid (W146)/3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W140) chiral pair is very useful; W146 is an S1P 1 antagonist and its enantiomer, W140, is an agonist at the same receptor (GonzalezCabrera et al, 2008). Although still not well studied, it was reported that 2-undecyl-thiazolidine-4-carboxylic acid (CAY10444) is a specific S1P 3 antagonist (Koide et al, 2007). The success of FTY720 in the clinic has spurred the search for similar molecules, particularly with S1P 3 -sparing activity.…”

Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P3 Receptor: Investigation Based on a New S1P3 Receptor Antagonist

“…Chinese hamster ovary K1 cells that stably expressed human S1P 1 (S1P 1 -CHO), S1P 2 (S1P 2 -CHO), or S1P 3 (S1P 3 -CHO) receptors were maintained as described previously (Koide et al, 2007). A human recombinant S1P 4 receptor-expressing cell line (S1P 4 -Chem) was purchased from Millipore.…”

“…Human coronary artery smooth muscle cells (HCASMCs) purchased from Kurabo were cultured in HuMedia-SG2. [Ca 2ϩ ] i in S1P 1 -, S1P 2 -, S1P 3 -CHO, and S1P 4 -Chem was measured using the calcium-sensitive dye Fura-2 acetoxymethyl ester, as described previously (Koide et al, 2007). The fluorescence (excitation at 340 and 380 nm, emission at 510 nm) was measured with a FLEXStation II (Molecular Devices, Sunnyvale, CA).…”