title: Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile).
abstract: Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: John A
authors.initials: JA
authors.lastname: Christopher
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Aves
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Kirstie A
authors.initials: KA
authors.lastname: Bennett
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Doré
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: James C
authors.initials: JC
authors.lastname: Errey
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Ali
authors.initials: A
authors.lastname: Jazayeri
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Okrasa
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Serrano-Vega
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Tehan
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Giselle R
authors.initials: GR
authors.lastname: Wiggin
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire AL7 3AX, U.K.
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D018938:Caco-2 Cells; D004285:Dogs; D015195:Drug Design; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C000602649:3-chloro-5-(6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)benzonitrile; C578937:Grm5 protein, rat; D008024:Ligands; D011725:Pyridines; D011743:Pyrimidines; D064529:Receptor, Metabotropic Glutamate 5; D043562:Receptors, G-Protein-Coupled