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.
Subject(s)
Anti-Obesity Agents/pharmacology , Indoles/pharmacology , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Animals , Anti-Obesity Agents/chemistry , Indoles/chemistry , RatsABSTRACT
A number of thiazolyl indolequinones have been prepared and evaluated for their antitumor properties. The compounds were synthesized from the appropriate indole, building up the thiazole ring using the Hantzsch reaction. Cytotoxic activity was determined in the human breast cancer SKBr3 cell line. Selected compounds were also studied in human lung carcinoma A549 and PV9 cell lines. In addition, some compounds were evaluated for their possible bioreductive action by determining their cytotoxicity towards V79 Chinese hamster lung fibroblasts in air and under anaerobic (hypoxic) conditions.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemical synthesis , Quinones/chemical synthesis , Thiazoles/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , CHO Cells , Cell Line , Cricetinae , Drug Screening Assays, Antitumor , Humans , Indoles/pharmacology , Lung Neoplasms/drug therapy , Magnetic Resonance Spectroscopy , Mass Spectrometry , Quinones/pharmacology , Spectrophotometry, Infrared , Thiazoles/pharmacology , Tumor Cells, CulturedABSTRACT
A number of indolyl thiazoles have been prepared and evaluated for their antitumor properties. The compounds were synthesized from the appropriate indole, building up the thiazole ring using the Hantzsch reaction. Cytotoxic activity was measured in the human breast cancer cell line SKBr3 using the MTT assay.
