Novel 2,7-Diazaspiro[4,4]nonane Derivatives to Inhibit Mouse and Human Osteoclast Activities and Prevent Bone Loss in Ovariectomized Mice without Affecting Bone Formation

Osteoporosis is currently treated
with drugs targeting the differentiation
or viability osteoclasts, the cells responsible for physiological
and pathological bone resorption. Nevertheless, osteoporosis drugs
that target only osteoclast activity are expected to preserve bone
formation by osteoblasts in contrast to current treatments. We report
here the design, synthesis, and biological characterization of a series
of novel N-arylsufonamides featuring a diazaspiro­[4,4]­nonane
nucleus to target the guanine nucleotide exchange activity of DOCK5,
which is essential for bone resorption by osteoclasts. These compounds
can inhibit both mouse and human osteoclast activity. In particular,
4-chlorobenzyl-4-hydroxy-2-phenyl-1-thia-2,7-diazaspiro­[4,4]­nonane
1,1-dioxide (compound E197) prevented pathological bone
loss in mice. Most interestingly, treatment with E197 did not affect osteoclast and osteoblast numbers and hence did not
impair bone formation. E197 could represent a lead molecule
to develop new antiosteoporotic drugs targeting the mechanism of osteoclast
adhesion onto the bone.