Selection, synthesis, and structure-activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists.
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.
Lanier
Marion C
MC
Departments of Medicinal Chemistry and Pharmacology, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. mlanier@neurocrine.com
Feher
Miklos
M
Ashweek
Neil J
NJ
Loweth
Colin J
CJ
Rueter
Jaimie K
JK
Slee
Deborah H
DH
Williams
John P
JP
Zhu
Yun-Fei
YF
Sullivan
Susan K
SK
Brown
Michael S
MS
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
D005021:Ethylamines; D011743:Pyrimidines; D011966:Receptors, LHRH; D006859:Hydrogen; C030986:pyrimidine; C041564:ethylamine