Subsequently, more complex and potent compounds were produced by the insertion of a primary, secondary, or tertiary nitrogen function in the R2 side chain, for example, pamidronate (PAM), alendronate (ALN), ibandronate (IBA), and incadronate (INC), which have an alkyl R2 side chain, or risedronate (RIS), zoledronate (ZOL), and minodronate (MIN), which have heterocyclic rings in the R2 side Inhibitors,research,lifescience,medical chain (Figure 2). Variation of

the substituents modulates the pharmacologic properties and gives each molecule its unique profile [7]. 2. Intracellular Effect and Pharmacodynamics of Bisphosphonates Extensive structure/activity studies have resulted in several very useful drugs that Inhibitors,research,lifescience,medical combine potent inhibition of osteoclastic bone resorption with good clinical tolerability [5–8]. The pronounced selectivity of BPs for bone rather than other tissues is the basis for their value in clinical practice. The antiresorptive effect cannot be accounted simply by adsorption of BPs to bone mineral and prevention of hydroxyapatite dissolution. It Axitinib melanoma became clear that BPs must inhibit bone resorption by cellular effects on osteoclasts rather than simply by physicochemical mechanisms [5]. Bisphosphonate moiety

and R1 group are both essential for hydroxyapatite Inhibitors,research,lifescience,medical affinity [8]. The BPs bind to hydroxyapatite crystals in the area of osteoclast-mediated Inhibitors,research,lifescience,medical bone erosion; during resorption, the dissolution of hydroxyapatite crystals by osteoclast determines the consequent release of the bisphosphonate that

may indeed come into contact with osteoclasts and inhibit their absorption capacity [8]. Incorporation of an aminoalkyl side chain at R2 increases antiresorptive potency by 10-fold; also, the length of carbon chain is important (alendronate is about 1000-fold more Inhibitors,research,lifescience,medical potent than etidronate while pamidronate is only 100-fold more active than etidronate) [4, 8]. In addition, incorporation of a nitrogen heterocycle (third-generation agents) further enhances antiresorptive potency: the GSK-3 most active compound in this class is ZOL, a BP containing an imidazole ring, which is up to 10000-fold more potent than both CLO and ETI in some experimental systems. During bone resorption, BPs are probably internalized by endocytosis along with other products of resorption [4, 8]. Many studies have shown that BPs can affect osteoclast-mediated bone resorption in a variety of ways, including effects on osteoclast recruitment, differentiation, and resorptive activity, and may induce apoptosis [7]. Because mature, multinucleated osteoclasts are formed by the fusion of mononuclear precursors of hematopoietic origin, BPs could also inhibit bone resorption by preventing osteoclast formation, in addition to affecting mature osteoclasts.