Widler, Leo; Jaeggi, Knut A.; Glatt, Markus; Mueller, Klaus; Bachmann, Rolf; Bisping, Michael; Born, Anne-Ruth; Cortesi, Reto; Guiglia, Gabriela; Jeker, Heidi; Klein, Remy; Ramseier, Ueli; Schmid, Johann; Schreiber, Gerard; Seltenmeyer, Yves; Green, Jonathan R. published the artcile< Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa)>, Recommanded Product: 5-Isopropylthiazol-2-amine, the main research area is bisphosphonate derivative preparation structure bone resorption inhibitor osteoporosis; hypercalcemia Paget’s metastasis osteolysis osteoporosis bisphosphonate derivative preparation.
Bisphosphonates (BPs) are pyrophosphate analogs in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-di-Me analog, are about 10 times more potent than pamidronate. Extending one of the N-Me groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analog of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a Ph group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a Me group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED50 of 0.07 mg/kg in the TPTX in vivo assay after s.c. administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clin. development under the registered trade name Zometa. The results of the clin. trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget’s disease of bone, osteolytic metastases, and postmenopausal osteoporosis.
Journal of Medicinal Chemistry published new progress about Antiosteoporotic agents. 101080-15-3 belongs to class thiazole, and the molecular formula is C6H10N2S, Recommanded Product: 5-Isopropylthiazol-2-amine.
Referemce:
Thiazole | C3H3NS – PubChem,
Thiazole | chemical compound | Britannica