title: Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound.
abstract: We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D3 both in vivo in the thyroparathyroidectomized rat (ED50 0.072 microgram/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 microM). A comparison of the in vivo and in vitro inhibitory potencies of a total of nine bisphosphonates revealed an excellent correlation between the two assays (r = 0.97). CGP 42'446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1-34), parathyroid hormone-related protein (1-34), and recombinant human interleukin-1 beat. Short-term treatment of growing rats with CGP 42'H446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED50 1.7 micrograms/kg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED50 values 0.17 and 1.1 micrograms/kg SC, respectively), but there was no detectable effect on cortical bone. On a molar basis in this range of in vivo screening assays, CGP 42'H446 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 bisphosphonate for the suppression of the increased bone resorption associated with various diseases.
authors.affiliation: Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
authors.forename: J R
authors.initials: JR
authors.lastname: Green
authors.forename: K
authors.initials: K
authors.lastname: Müller
authors.forename: K A
authors.initials: KA
authors.lastname: Jaeggi
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001862:Bone Resorption / Q000139:chemically induced / Q000188:drug therapy*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006934:Hypercalcemia / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D010281:Parathyroid Hormone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D016105:Parathyroidectomy; D010446:Peptide Fragments / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D013965:Thyroidectomy; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D007375:Interleukin-1; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C054296:parathyroid hormone-related protein (1-34); D000077211:Zoledronic Acid; D002117:Calcitriol; D002118:Calcium