Selection, synthesis, and structure–activity relationship of tetrahydropyrido[4,3- d]pyrimidine-2,4-diones as human GnRH receptor antagonists

A series of tetrahydropyrido[4,3- d]pyrimidine-2,4-dione was selected in silico and evaluated as small molecules antagonists against the h-GnRH receptor. SAR is reported 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 10 nM for the h-GnRH receptor after two rounds of optimization.