title: Discovery of benzamides as potent human β3 adrenergic receptor agonists.
abstract: The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human β3-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 β3-adrenergic potency and good selectivity over the β1 and β2 receptors. In addition to human β1, β2, β3 and hERG data, PK of selected compounds will be described.
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: cheng.zhu@merck.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Nam F
authors.initials: NF
authors.lastname: Kar
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Costa
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Dingley
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Sookhee N
authors.initials: SN
authors.lastname: Ha
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Hurley
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Li
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Randy R
authors.initials: RR
authors.lastname: Miller
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Gino M
authors.initials: GM
authors.lastname: Salituro
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Struthers
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.affiliation: Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D001549:Benzamides; D022702:Receptors, Adrenergic, beta-3
keywords: Bioisostere; Overactive bladder; Pyrrolidine scaffold; Reverse amide; β(3) adrenergic receptor agonist