Novel potent antagonists of human neuropeptide Y Y5 receptor. Part 1: 2-oxobenzothiazolin-3-acetic acid derivatives.

Novel NPY-Y5 antagonist FR73966 was discovered by screening of our in-house chemical library. The analogues were prepared by application of parallel synthesis techniques. Some of the resulting 2-oxobenzothiazolin-3-acetic acid derivatives exhibited nanomolar binding affinity for human NPY-Y5 receptors.

Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives.

As a part of our continuing research on NPY-Y5 receptor antagonists in the series of novel 6-methoxybenzo[a]cycloheptene derivatives, we discovered a novel skeleton, 7-methoxy-1-hydroxytetraline 7 which had been used as an intermediate, to be more suitable for increasing potencies leading to compound 3 (FR230481). Additionally, we discovered that the naphthalenesulfonamide moiety which was thought to be an essential pharmacophore could be replaced by the 5-chlorobenzothiazolin-3-acetic acid moiety to lead to potent compound 4 (FR233118). The structure-activity relationships on compounds 3,4 and their related derivatives are described.

Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 2: substituted benzo[a]cycloheptene derivatives.

Novel benzo[a]cycloheptene derivatives were prepared for the purpose of searching new neuropeptide Y-Y5 (NPY-Y5) receptor antagonists. The structure-activity relationships are described and compound 2o (FR226928) showed the most potent affinity for Y5 receptor of all we prepared and was found to have higher potency and better selectivity for Y5 over Y1 receptor affinities when compared with the known lead compound 1.