BINDING AND ANTIRESORPTIVE PROPERTIES OF HETEROCYCLE-CONTAINING BISPHOSPHONATE ANALOGS - STRUCTURE-ACTIVITY-RELATIONSHIPS

To define structure-activity relationships for bisphosphonate activity , we examined the bone binding and antiresorptive properties of hetero cycle-containing analogs of risedronate, a pyridylbisphosphonate, in c ultures of mouse fetal bone explants. Our studies indicated that hydro xybisphosphonates with the nitrogen molecule in the pyridyl ring were very potent inhibitors of osteoclastic resorption, Changing the place of the nitrogen in the ring structure of risedronate or its methylatio n did not significantly alter antiresorptive potency in relation to ri sedronate, Extension of the R-2 chain, however, reduced efficacy. In b inding experiments, we found that all heterocyclic bisphosphonates wit h a hydroxyl group in R-1 had comparable affinity for bone mineral and inhibited calcium incorporation into bone explants to a similar exten t. The affinity of a risedronate analog without R-1 was markedly reduc ed. We also examined the properties of a risedronate analog (NE-10790) belonging to the group of phosphonocarboxylates in which one of the p hosphonate groups is substituted by a carboxyl group. NE-10790 had str ongly reduced binding affinity, but still retained some antiresorptive activity. Interestingly, the continuous presence of NE-10790 in cultu res of fetal mouse metacarpal bones increased its antiresorptive effic acy by about 40-fold compared with 24 h preincubation, whereas, under the same conditions, the potency of high-affinity hydroxybisphosphonat es did not change or only slightly increased. This may be explained by the differences in pharmacokinetic behavior between compounds of high and of low affinity for bone mineral, These data show that, as with a lkylbisphosphonates, heterocycle-containing bisphosphonates with a nit rogen functionality in the R-2 chain are potent antiresorptive agents and a hydroxyl substitution in the R-1 chain confers high affinity for bone mineral, probably due to tridentate configuration. The group of phosphonocarboxylates, with strongly reduced bone affinity, provides a n interesting therapeutic option. (C) 1998 by Elsevier Science Inc. Al l rights reserved.