title: QSAR design of triazolopyridine mGlu2 receptor positive allosteric modulators.
abstract: Two QSAR approaches were applied to assist the design and to prioritise the synthesis of new active mGlu2 receptor positive allosteric modulators (PAMs). With the aim to explore a particular point of substitution the models successfully prioritised molecules originating from chemistry ideas and a large virtual library. The two methods, 3D topomer CoMFA and support vector machines with 2D ECFP6 fingerprints, delivered good correlation and success in this prospective application. Fourteen molecules with different substituent decoration were identified by the in silico models and synthesised. They were found to be highly active and their mGlu2 receptor PAM activity (pEC50) was predicted within 0.3 and 0.4log units of error with the two methods. The value of the molecules and the models for the future of the project is discussed.
authors.affiliation: Discovery Sciences, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. Electronic address: gtresade@its.jnj.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Calle Jarama 75, Toledo 45007, Spain.
authors.forename: José-Maria
authors.initials: JM
authors.lastname: Cid
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research and Development, Calle Jarama 75, Toledo 45007, Spain.
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
mesh_terms: D000494:Allosteric Regulation; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry*
chemical_list: D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; C108822:metabotropic glutamate receptor 2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: Allosteric modulator; QSAR; SVM; Top-CoMFA; Topomer CoMFA