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Abstract
In 1986, a chemistry program was initiated to discover a more potent bisphosphonate as a follow-up to pamidronate for the treatment of osteoporosis and metastatic bone disease. Three subclasses of bisphosphonates were investigated: 1) analogues of pamidronate with different alkyl and phenyl-X-alkyl-substituents (X = O, S) at the nitrogen (tables 1 and 2); 2) hydroxy bisphosphonates with a five-membered heteroaromatic substitutent linked via a methylene bridge to C1 (table III); 3) aminomethylene bisphosphonates with a five-membered heteroaromatic substitutent (table IV). Zoledronate was selected for development based on its high antiresorptive activity, good dissociation from inhibition of bone mineralization and excellent renal tolerability. Preliminary results from Phase I clinical trials have confirmed the compound's predicted profile.
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