title: N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists.
abstract: Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K(i) 4 nM vs 1a 27 nM) and microsomal stability (human CL(int) 2.5 L/min vs 1a 35L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K(i) 9 nM, B/P 520/840 nM 10 mg/kg PO).
authors.affiliation: Department of Chemical & Pharmacokinetic Sciences, 215 College Road, Paramus, NJ 07652, USA. lwu@lundbeck.com
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.forename: Kai
authors.initials: K
authors.lastname: Lu
authors.forename: Mahesh
authors.initials: M
authors.lastname: Desai
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Packiarajan
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Marzabadi
authors.forename: Vrej
authors.initials: V
authors.lastname: Jubian
authors.forename: Kim
authors.initials: K
authors.lastname: Andersen
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.forename: Noel J
authors.initials: NJ
authors.lastname: Boyle
authors.forename: Mary W
authors.initials: MW
authors.lastname: Walker
mesh_terms: D000588:Amines / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D006571:Heterocyclic Compounds; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; C018556:glycine amide; D005998:Glycine