Serotonin (5-HT) is known to be associated with fibrosis and recent studies support that 5-HT2B receptors have an important role in fibrotic disease by regulating production of pro-fibrotic mediators and modifying cell differentiation and activation. Most 5-HT2B receptor antagonist developed so far are associated with certain liabilities, such as poor selectivity and inadequate pharmacokinetic properties. Starting from benzylidene-aminoguanidine derivatives, e.g. Guanabenz, an unselective a2-adrenergic agonist with moderate 5-HT2B receptor binding, we have developed new, highly potent and selective antagonists of the 5-HT2B receptor. The lead compound (Compound-A) was prepared in two synthetic steps, a Mannich reaction and a ring-forming condensation reaction with aminoguanidine, followed by chiral separation. Compound-A is a potent and selective 5-HT2B receptor antagonist (IC50 2.4 nM, Mw 218) with no agonistic effect at 10 uM and with high aqueous solubility (&gt;10 mg/mL), and has been shown effective both in in vitro and in vivo models of fibrosis. Here we report on the synthetic preparation and the very robust SAR of the 5-HT2B receptor binding for this compound class. Variations of the aromatic substituents, the pyrazoline regio- and stereochemistry, and the guanidine moiety all have major and distinct impact on the receptor binding. Virtual docking to the 5-HT2B receptor was used to guide the compound development providing high affinity ligands (IC50 0.1-1 nM).

New selective 5-HT2B receptor antagonists for the treatment of fibrosis

254th National Meeting (2017)

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