Bisphosphonate Prodrugs

Abstract

Bisphosphonates (BP) are pyrophosphate analogs having a P-C-P backbone. The oral bioavailability of BPs is ca. 1%, due to high ionisation at physiological pH. Using the prodrug approach, oral absorption can be increased by masking one or more ionizable groups (clodronate, etidronate), or using a targeting carrier system (alendronate, pamitronate).

Synthesis and biological evaluation of novel bisphosphonates with dual activities on bone in vitro

“…On the other hand, structure-activity relationship (SAR) studies of bisphosphonates have demonstrated that nitrogen-containing bisphosphonates are more potent inhibitors of bone resorption, and furthermore, introduction of a cyclic group on the side chain may increase the anti-resorptive potency. 7 Therefore, we designed and synthesized a new type of bisphosphonates with various aromatic rings on the side chains linked by amide bonds (Fig. 2).…”

Synthesis of new indole-based bisphosphonates and evaluation of their chelating ability in PE/CA-PJ15 cells

“…Indeed, they lack the acid features, although compounds 1aef could act as prodrugs with subsequent ester cleavage. Other attempts to synthesized BPs prodrugs have been proposed [25] suggesting that several groups (such as carboxylic esters, amides, anhydrides) can be used to functionalize the acid phosphate in order to improve the compound's oral bioavailability. The presence of the indole scaffold and the esterification of the bisphosphonate moiety also results in a significant increase of the LogP value.…”

Methyl [hydroxy(phenyl)phosphonomethyl]phosphonate methanol solvate

“…For related literature, see: Barbey et al (2003), Migianu et al (2005), Fleisch (1998Fleisch ( , 2002; Clezardin et al (2003); Green & Clezardin (2002); Lecouvey et al (2003a,b); Vepsalainen (2002 Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) x; y þ 1; z; (ii) Àx þ 1; Ày; Àz; (iii) x; y À 1; z; (iv) x þ 1; y; z.…”

“…Moreover, they induce some secondary effects such as gastric and intestinal problems and osteonecrosis of the jaw-bone. To circumvent to these drawbacks, a prodrug strategy was considered that would deliver bisphosphonates with an improved gastrointestinal absorption (Vepsalainen, 2002). The approach in our laboratory consists of modifying the phosphonic acid functionality itself, by introducing an ester group (Lecouvey et al, 2003a,b).…”