5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides:  Novel and Selective Inhibitors of the Vacuolar H⁺-ATPase of Osteoclasts with Bone Antiresorptive Activity

Abstract

The vacuolar H+-ATPase (V-ATPase), located on the ruffled border of the osteoclast, is a proton pump which is responsible for secreting the massive amounts of protons that are required for the bone resorption process. With the aim to identify new agents which are able to prevent the excessive bone resorption associated with osteoporosis, we have designed a novel class of potent and selective inhibitors of the osteoclast proton pump, starting from the structure of the specific V-ATPase inhibitor bafilomycin A1. Compounds 3a-d potently inhibited the V-ATPase in chicken osteoclast membranes (IC50 = 60-180 nM) and were able to prevent bone resorption by human osteoclasts in vitro at low-nanomolar concentrations. Notably, the EC50 of compound 3c in this assay was 45-fold lower than the concentration required for half-maximal inhibition of the V-ATPase from human kidney cortex. These results support the validity of the osteoclast proton pump as a useful molecular target to produce novel inhibitors of bone resorption, potentially useful as antiosteporotic agents.

Inhibitors of V-ATPases: old and new players

“…This allowed the design and synthesis of novel indole derivatives as structurally simpler V-ATPase inhibitors (Gagliardi et al, 1998b). The most potent inhibitor, with an IC 50 of 30 nmol l -1…”

“…The aim of this current review is to illustrate recent advances in the field, to present an update on the old players in the inhibition game, the plecomacrolides bafilomycin and concanamycin, and to introduce some of the new players, the macrolactone archazolid (Sasse et al, 2003), the benzolactone enamides salicylihalamide, lobatamide, apicularen, oximidine and cruentaren (Erickson et al, 1997;Galinis et al, 1997;Kim et al, 1999;Kunze et al, 1998;Kunze et al, 2006), and the indolyls (Gagliardi et al, 1998b;Nadler et al, 1998). Obviously this cast is not complete and, therefore, the specific V-ATPase inhibitors, which are not the focus of this review, are briefly mentioned here.…”

Use of Acid-Suppressive Drugs and Risk of Fracture: A Meta-analysis of Observational Studies

“…[7][8][9][10][11] Osteoclasts possess proton pumps, which are used during the excretion of H+ ions for bone resorption. Osteoclast-selective PPIs may therefore be used as antiresorptive agents 12 with the potential of preventing fractures. [13][14][15][16] Administration of a selective inhibitor of the osteoclastic vacuolar H+/ K+ ATPase prevents bone loss in ovariectomized rats, an animal model representative of postmenopausal osteoporosis.…”

Mutations in Subunit c of the Vacuolar ATPase Confer Resistance to Bafilomycin and Identify a Conserved Antibiotic Binding Site

“…For example, considerable effort has been made to develop bafilomycin derivatives for the treatment of osteoporosis (11)(12)(13)(14). Bafilomycin and concanamycin are also potent anti-tumor agents that exhibit significant cell line specificity (15).…”