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 Figure 2 and Scheme 1 (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 Figure 2 and Scheme 2 (FR233118). The structure–activity relationships on compounds Figure 2 and Scheme 2 and their related derivatives are described. Unfortunately, although compounds Figure 2 and Scheme 1 and Figure 2 and Scheme 2 had very high affinities for Y5 receptors, their poor permeabilities to brain were shown by exo-vivo binding assays when orally administered.