title: Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human β3 adrenergic receptor agonists.
abstract: A novel class of human β(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β(3)-AR agonists. As observed, many of the β(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human β(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional β(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new β(3)-AR agonists containing the pyrrolidine moiety.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA. greg_morriello@merck.com
authors.forename: Gregori J
authors.initials: GJ
authors.lastname: Morriello
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Wendt
authors.forename: Alka
authors.initials: A
authors.lastname: Bansal
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.forename: Scott
authors.initials: S
authors.lastname: Feighner
authors.forename: Jiafang
authors.initials: J
authors.lastname: He
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Hurley
authors.forename: Donna L
authors.initials: DL
authors.lastname: Hreniuk
authors.forename: Gino M
authors.initials: GM
authors.lastname: Salituro
authors.forename: Marat Vijay
authors.initials: MV
authors.lastname: Reddy
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Galloway
authors.forename: Katherine K
authors.initials: KK
authors.lastname: McGettigan
authors.forename: George
authors.initials: G
authors.lastname: Laws
authors.forename: Crystal
authors.initials: C
authors.lastname: McKnight
authors.forename: George A
authors.initials: GA
authors.lastname: Doss
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Regina M
authors.initials: RM
authors.lastname: Black
authors.forename: Judy
authors.initials: J
authors.lastname: Morris
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Sanfiz
authors.forename: Eric
authors.initials: E
authors.lastname: Streckfuss
authors.forename: Mary
authors.initials: M
authors.lastname: Struthers
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
mesh_terms: D000318:Adrenergic beta-Agonists / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry*; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D011759:Pyrrolidines; D022702:Receptors, Adrenergic, beta-3