title: Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).
abstract: Novel in vitro mGlu(5) positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC(50) 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC(50) 156.3 nM). Derivation of a second-generation of mGlu(5) PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8-azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC(50) 50.1 nM) as a potent and soluble mGlu(5) PAM devoid of both undesirable phenylacetylene and carbonyl functionalities.
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA. jeffrey.varnes@astrazeneca.com
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Marcus
authors.forename: Russell C
authors.initials: RC
authors.lastname: Mauger
authors.forename: Scott R
authors.initials: SR
authors.lastname: Throner
authors.forename: Valerie
authors.initials: V
authors.lastname: Hoesch
authors.forename: Megan M
authors.initials: MM
authors.lastname: King
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Linda A
authors.initials: LA
authors.lastname: Sygowski
authors.forename: Nathan
authors.initials: N
authors.lastname: Spear
authors.forename: Reto
authors.initials: R
authors.lastname: Gadient
authors.forename: Dean G
authors.initials: DG
authors.lastname: Brown
authors.forename: James B
authors.initials: JB
authors.lastname: Campbell
mesh_terms: D000494:Allosteric Regulation; D015195:Drug Design; D020128:Inhibitory Concentration 50; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate