Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists

Abstract A series of 9-disubstituted N -(9 H -fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT 2B and 5-HT 7 receptor antagonists. Upon screening several compounds, N -(diaminomethylene)-4′,5′-dihydro-3′ H -spiro[fluorene-9,2′-furan]-2-carboxamide ( 17 ) exhibited potent affinity for both 5-HT 2B ( K i  = 5.1 nM) and 5-HT 7 ( K i  = 1.7 nM) receptors with high selectivity over 5-HT 2A , 5-HT 2C , α 1 , D 2 and M 1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds ( R )- 17 and ( S )- 17 . Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. ( R )- 17 and ( S )- 17 were therefore selected as candidates for human clinical trials.