title: Selection, synthesis, and structure-activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists.
abstract: The present article describes a selection of a new class of small molecule antagonists for the h-GnRH receptor, their preparation, and evaluation in vitro. Three computational methods were combined into a consensus score, to rank order virtual templates. The top 5% of templates were further evaluated in silico and assessed for novelty and synthetic accessibility. The tetrahydropyrido[4,3-d]pyrimidine-2,4-dione core was selected for synthesis and evaluated in vitro. Using an array approach for analog design and synthesis, we were able to drive the binding below 10nM for the h-GnRH receptor after two rounds of optimization.
authors.affiliation: Departments of Medicinal Chemistry and Pharmacology, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. mlanier@neurocrine.com
authors.forename: Marion C
authors.initials: MC
authors.lastname: Lanier
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ashweek
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Loweth
authors.forename: Jaimie K
authors.initials: JK
authors.lastname: Rueter
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Slee
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Susan K
authors.initials: SK
authors.lastname: Sullivan
authors.forename: Michael S
authors.initials: MS
authors.lastname: Brown
mesh_terms: D016208:Databases, Factual; D005021:Ethylamines / Q000737:chemistry; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D005021:Ethylamines; D011743:Pyrimidines; D011966:Receptors, LHRH; D006859:Hydrogen; C030986:pyrimidine; C041564:ethylamine