title: Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5.
abstract: A novel series of diaryl bicyclic azole-amines that are potent selective negative modulators of metabotropic glutamate receptor 5 (mGluR5) were identified through rational design. An initial hit compound 5a of modest potency (IC(50) = 1.2 μM) was synthesized. Evaluation of structure-activity relationships (SAR) on the left-hand side of the molecule revealed a preference for a 2-substituted pyridine group linked directly to the central heterocycle. Variation of the central azolo-amine portion of the molecule revealed a preference for the [4,5-c]-oxazoloazepine scaffold, while right-hand side variants showed a preference for ortho- and meta-substituted benzene rings linked directly to the tertiary amine of the saturated heterocycle. These iterations led to the synthesis of 29b, a potent (IC(50) = 16 nM) and selective negative modulator that showed good brain penetrance, high receptor occupancy, and a duration of action greater than 1 h in rat when administered intraperitoneally. Formal PK studies in rat and Rhesus monkey revealed a short half-life that was attributable to high first-pass clearance.
authors.affiliation: Discovery & Early Clinical Research, Sepracor Inc., 84 Waterford Drive, Marlborough, Massachusetts 01752, USA. douglas.burdi@sepracor.com
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Burdi
authors.forename: Rachel
authors.initials: R
authors.lastname: Hunt
authors.forename: Lei
authors.initials: L
authors.lastname: Fan
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Zihong
authors.initials: Z
authors.lastname: Guo
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Huang
authors.forename: Chengde
authors.initials: C
authors.lastname: Wu
authors.forename: Larry
authors.initials: L
authors.lastname: Hardy
authors.forename: Michel
authors.initials: M
authors.lastname: Detheux
authors.forename: Michael A
authors.initials: MA
authors.lastname: Orsini
authors.forename: Maria S
authors.initials: MS
authors.lastname: Quinton
authors.forename: Robert
authors.initials: R
authors.lastname: Lew
authors.forename: Kerry
authors.initials: K
authors.lastname: Spear
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D015195:Drug Design; D018683:Excitatory Amino Acid Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C553291:3-fluoro-5-(2-(pyridin-2-yl)-7,8-dihydro-4H-oxazolo(4,5-c)azepin-5(6H)-yl)benzonitrile; D001381:Azepines; D018683:Excitatory Amino Acid Agents; C578937:Grm5 protein, rat; D006574:Heterocyclic Compounds, 2-Ring; D009570:Nitriles; D010080:Oxazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate