Bone active bisphosphonate mechanistic studies: Synthesis of a 2-pyrindinylmethylene bisphosphonic acid via a photolytic ring contraction

Recent research on the bone active bisphosphonate class of drugs has led to highly potent nitrogen-containing analogs. The involvement of specific cel lular targets and therefore a critical bisphosphonate pharmacophore require d in the mechanism of inhibition of bone resorption is suggested To further test this concept, the successful design of a potent conformationally rest ricted analog, based on the structure-activity relationships deduced from t his research, has been accomplished via the preparation of a 2-pyrindinylme thylene bisphosphonate NE-10501 (3). An interesting photolytic ring contrac tion was utilized as the key step in the synthesis of this novel bone activ e compound. (C) 2000 John Wiley & Sons, Inc.