ABSTRACT
The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human ß3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established ß3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.
Subject(s)
Adrenergic beta-3 Receptor Agonists/pharmacology , Piperazines/pharmacology , Urinary Bladder, Overactive/drug therapy , Adrenergic beta-3 Receptor Agonists/chemistry , Adrenergic beta-3 Receptor Agonists/therapeutic use , Humans , Piperazines/chemistry , Piperazines/therapeutic use , Structure-Activity RelationshipABSTRACT
The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human ß3-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human ß3-adrenergic potency and good selectivity over the ß1 and ß2 receptors. In addition to human ß1, ß2, ß3 and hERG data, PK of selected compounds will be described.
