Molecular features crucial to the activity of pyrimidine benzamide-based thrombopoietin receptor agonists.
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.
Reiter
Lawrence A
LA
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
Jones
Christopher S
CS
Brissette
William H
WH
McCurdy
Sandra P
SP
Abramov
Yuriy A
YA
Bordner
Jon
J
DiCapua
Frank M
FM
Munchhof
Michael J
MJ
Rescek
Diane M
DM
Samardjiev
Ivan J
IJ
Withka
Jane M
JM
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
D001549:Benzamides; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; C037689:benzamide; D013926:Thrombopoietin; C030986:pyrimidine