ABSTRACT
Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.
Subject(s)
Pyrazines/chemistry , Pyrazines/pharmacology , Pyrroles/chemistry , Serotonin 5-HT2 Receptor Agonists , Animals , CHO Cells , Cricetinae , Humans , Hydroxylation , Molecular Structure , Phospholipids/pharmacology , Pyrazines/chemical synthesis , Receptor, Serotonin, 5-HT2C/genetics , Receptor, Serotonin, 5-HT2C/metabolism , Structure-Activity RelationshipABSTRACT
A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.
