title: Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.
abstract: A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.
authors: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. haoju@lilly.com
authors: Junliang
authors: J
authors: Hao
authors: Veronique
authors: V
authors: Dehlinger
authors: Adam M
authors: AM
authors: Fivush
authors: Helene C E
authors: HC
authors: Rudyk
authors: Thomas C
authors: TC
authors: Britton
authors: Sean P
authors: SP
authors: Hollinshead
authors: Benjamin P
authors: BP
authors: Vokits
authors: Barry P
authors: BP
authors: Clark
authors: Steven S
authors: SS
authors: Henry
authors: Steven M
authors: SM
authors: Massey
authors: Langu
authors: L
authors: Peng
authors: Bruce A
authors: BA
authors: Dressman
authors: Beverly A
authors: BA
authors: Heinz
authors: Edda F
authors: EF
authors: Roberts
authors: Mallorie R
authors: MR
authors: Bracey-Walker
authors: Steven
authors: S
authors: Swanson
authors: John T
authors: JT
authors: Catlow
authors: Patrick L
authors: PL
authors: Love
authors: Anita D
authors: AD
authors: Tepool
authors: Steven C
authors: SC
authors: Peters
authors: Rosa Maria A
authors: RM
authors: Simmons
authors: Smriti
authors: S
authors: Iyengar
authors: David L
authors: DL
authors: McKinzie
authors: James A
authors: JA
authors: Monn
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003521:Cyclopropanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D007191:Indazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000577:Amides; D003521:Cyclopropanes; C578937:Grm5 protein, rat; D007191:Indazoles; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; D018698:Glutamic Acid; C538819:cyclopropanecarboxamide