title: CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor.
abstract: The metabotropic glutamate receptor 5 (mGlu5) is a glutamate-activated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinson's disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [(3)H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED(50) equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30- to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.
authors.affiliation: F. Hoffmann-La Roche Ltd. Pharmaceuticals Division, Discovery Neuroscience, Grenzacherstrasse 124, 4070 Basel, Switzerland. lothar.lindemann@roche.com
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.forename: Aubin
authors.initials: A
authors.lastname: Michalon
authors.forename: Eric
authors.initials: E
authors.lastname: Vieira
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Richard
authors.initials: R
authors.lastname: Porter
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Sabine
authors.initials: S
authors.lastname: Kolczewski
authors.forename: Bernd
authors.initials: B
authors.lastname: Büttelmann
authors.forename: Christophe
authors.initials: C
authors.lastname: Flament
authors.forename: Catherine
authors.initials: C
authors.lastname: Diener
authors.forename: Christophe
authors.initials: C
authors.lastname: Fischer
authors.forename: Silvia
authors.initials: S
authors.lastname: Gatti
authors.forename: Eric P
authors.initials: EP
authors.lastname: Prinssen
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hoffmann
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005334:Fever / Q000188:drug therapy*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D010957:Plasmids; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors*
chemical_list: C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; D014151:Anti-Anxiety Agents; D007093:Imidazoles; D007295:Inositol Phosphates; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000242:Cyclic AMP; D002118:Calcium