Takeuchi M, Sakamoto S, Kawamuki K, Kurihara H, Nakahara H, Isomura Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1998 Nov;46(11):1703-9. doi: 10.1248/cpb.46.1703.
Two new series of fused aza-heteroarylbisphosphonates (5, 8), which are structurally quite different from incadronate (YM175), and related compounds were synthesized and evaluated for antiresorptive activity using a parathyroid hormone(PTH)-induced hypercalcemia model in rats (PIH model). Among these compounds, several exhibited more potent antiresorptive activity than pamidronate. In particular, [1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene]bisphosphonic acid (5b, minodronate) was 100-fold more potent than pamidronate in not only the PIH model, but also in an immobilization bone atrophy model in rats (DA model), and was selected for clinical development. The structure-activity relationships in these new series of bisphosphonates are discussed.
