ABSTRACT
Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.
Subject(s)
Cyclohexanes/chemistry , Indans/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Benzimidazoles/chemistry , Half-Life , Indans/metabolism , Indans/pharmacokinetics , Isomerism , Mice , Protein Binding , Rats , Receptors, Pituitary Hormone/metabolismABSTRACT
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Subject(s)
Indans/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Crystallography, X-Ray , Humans , Indans/chemistry , Indans/pharmacokinetics , Kinetics , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents have been identified. These compounds show non-selective inhibitory properties against a panel of protein tyrosine phosphatases including PTP1B. Compounds 12 and 13 display oral glucose lowering effects in ob/ob mice.
