title: Molecular features crucial to the activity of pyrimidine benzamide-based thrombopoietin receptor agonists.
abstract: The identification of small molecule modulators of biological processes mediated via protein-protein interactions has generally proved to be a challenging endeavor. In the case of the thrombopoietin receptor (TPOr), however, a number of small molecule types have been reported to display biological activity similar to that of the agonist protein TPO. Through a detailed analysis of structure-activity relationships, X-ray crystal structures, NMR coupling constants, nuclear Overhauser effects, and computational data, we have determined the agonism-inducing conformation of one series of small molecule TPOr agonists. The relationship of this agonism-inducing conformation to that of other series of TPO receptor agonists is discussed.
authors.affiliation: Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: William H
authors.initials: WH
authors.lastname: Brissette
authors.forename: Sandra P
authors.initials: SP
authors.lastname: McCurdy
authors.forename: Yuriy A
authors.initials: YA
authors.lastname: Abramov
authors.forename: Jon
authors.initials: J
authors.lastname: Bordner
authors.forename: Frank M
authors.initials: FM
authors.lastname: DiCapua
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.forename: Diane M
authors.initials: DM
authors.lastname: Rescek
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Samardjiev
authors.forename: Jane M
authors.initials: JM
authors.lastname: Withka
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013926:Thrombopoietin / Q000737:chemistry / Q000378:metabolism
chemical_list: D001549:Benzamides; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; C037689:benzamide; D013926:Thrombopoietin; C030986:pyrimidine