Description
Neridronic acid was launched in Italy as intravenous or intramuscular injection for the
treatment of osteogenesis imperfecta. It is the first drug launched worldwide for this
“orphan disease” characterized by a fragility of the bone. Sufferers risk frequent fractures
commencing during infancy, eventually leading to bone deformation and a severe
deterioration of the quality of life and life expectancy. Neridronic acid is structurally related
to the second generation of bisphosphonates characterized by an amino terminal group
and can be synthesized by treating E-aminocaproic acid with phosphoric acid and
phosphorous trichloride. Bisphosphonates, synthetic analogs of the endogenous mineral
deposition inhibitor pyrophosphate, are extremely potent inhibitors of bone resorption and
increase bone mineral density, possibly by inhibiting the activity of osteoclasts and
promoting the death of these bone-eroding cells. In vitro, neridronic acid was a poor
inhibitor of phagocytosis, but significantly and dose dependently inhibited 8glucuronidase
release and superoxide anion production in the rat peritoneal macrophage, two parameters
that may have a part in bone resorption. In a clinical study on patients with osteogenesis
imperfecta, neridronic acid increased remarkably bone mass in young growing individuals.
In adults the changes were less important but still significant.
Description
Neridronic acid is an amino bisphosphonate that inhibits farnesyl pyrophosphate (FPP) synthase (IC
50 = 388.2 nM in a cell-free assay). It decreases the differentiation of RAW 264.7 cells into osteoclasts in a CRL-12257 co-culture model of osteoclastogenesis when used at concentrations ranging from 0.001 to 100 μM. Neridronic acid (30 μM) inhibits FGF2-induced proliferation and tube formation in human umbilical vein endothelial cells (HUVECs). It reduces the loss of trabeculae and increases bone density in the tibial metaphysis of growing rats when administered subcutaneously at a dose of 0.1 mg/kg per day.
Originator
lnstituto Gentili (Italy)
Definition
ChEBI: Neridronic acid is a 1,1-bis(phosphonic acid).
Biochem/physiol Actions
Neridronate is a bone resorption inhibitor. It is used to treat Osteogenesis Imperfecta, an "orphan disease" characterized by a fragility of the bone enough to be named the "illness of bones of crystal".
Synthesis
6-
Aminohexanoic acid (152) was reacted with phosphorus
trichloride and phosphorous acid at 85C, and then water was added to generate free diphosphonic acid 16 in 78%
overall yield [59].
References
[1] JAMES E. DUNFORD*. Structure–Activity Relationships Among the Nitrogen Containing Bisphosphonates in Clinical Use and Other Analogues: Time-Dependent Inhibition of Human Farnesyl Pyrophosphate Synthase[J]. Journal of Medicinal Chemistry, 2008, 51 7: 2187-2195. DOI:
10.1021/jm7015733[2] VANESSA NICOLIN . Effects of neridronic acid on osteoclasts derived by physiological dual-cell cultures[J]. Acta histochemica, 2007, 109 5: Pages 397-402. DOI:
10.1016/j.acthis.2007.04.002[3] D RIBATTI. Neridronate inhibits angiogenesis in vitro and in vivo.[J]. Clinical Rheumatology, 2007: 1094-1098. DOI:
10.1007/s10067-006-0455-3[4] R SCHENK. Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat.[J]. Calcified Tissue International, 1986, 38 6: 342-349. DOI:
10.1007/bf02555748
