Calcium-sensing receptor (CaSR) antagonism has been recognized as a promising target of anabolic agents for treating osteoporosis. We first discovered a novel structural class of tetrahydropyrazolopyrimidine derivatives containing an adamantyl group with potent CaSR antagonistic activity as a lead series. However this compound did not stimulate transient PTH secretion due to poor pharmacokinetic profiles. In order to address the issue, we introduced the gem-dialkyl benzyl group as a bioisostere of the adamantyl group. Further optimization led to the discovery of TAK-075, which stimulates transient PTH secretion, as a potent and orally available CaSR antagonist. The design, structure-activity relationship (SAR) and in vivo animal studies will be presented.

Novel and potent calcium sensing receptor antagonists: Discovery of TAK-075 as an orally active bone anabolic agent

241st National Meeting (2011)

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