PRECLINICAL PHARMACOLOGY OF CGP 42'446, A NEW, POTENT, HETEROCYCLIC BISPHOSPHONATE COMPOUND

We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1, 1-bisp hosphonate], on bone metabolism. The compound exhibited potent inhibit ory activity on the bone resorption induced by 1,25-dihydroxyvitamin D -3 both in vivo in the thyroparathyroidectomized rat (ED(50) 0.072 mu g/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 mu M). A comparison of the in vivo and in vitro inhibitory potencies of a tota l of nine bisphosphonates revealed an excellent correlation between th e two assays (r = 0.97). CGP 42'446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1-34), parathyroid hor mone-related protein (1-34), and recombinant human interleukin-1 beta. Short-term treatment of growing rats with CGP 42'446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED(50) 1.7 mu g/kg SC) as well as increasing the calcium and hydroxyp roline content of femoral trabeculae (ED(50) values 0.17 and 1.1 mu g/ kg SC, respectively), but there was no detectable effect on cortical b one. On a molar basis in this range of in vivo screening assays, CGP 4 2'446 was between 940-fold (thyroparathyroidectomized rat) and 87-fold (rat femoral trabecular calcium content) more potent than pamidronate . It is concluded that CGP 42'446 is a promising new, highly potent bi sphosphonate for the suppression of the increased bone resorption asso ciated with various diseases.