- IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS
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A method for the treatment of diseases related to loss of bone mass such as osteoporosis, Paget's disease of bone, hy-perparathyroidism, malignant neoplasms causing hypercalcinemia, parodontal diseases and implant-related bone loss comprising administration to a patient suffering thereform an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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- Antiulcer Agents. 2. Gastric Antisecretory, Cytoprotective, and Metabolic Properties of Substituted Imidazolpyridines and Analogues
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The search for a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazopyridine, Sch 28080 (27), a compound that exhibits gastric antisecretory and cytoprotective properties and has undergone clinical evaluation as an antiulcer agent, has culminated in the identification of four related compounds that exhibit pharmacologic profiles similar to that of 27.In three of these potential successors an amino group functions as a surrogate for the 3-cyanomethyl substituent of the prototype.The present work concerns, in addition to an evaluation of the structure-activity relationships of a series of analogues of 27, preliminary studies of the pharmacodynamics and metabolism of 27, performed with the aid of cyano carbon labeled versions of the drug (13C labeled; 28; 14C labeled, 29).These studies have shown that 27 is well-absorbed and extensively metabolized and that the major metabolite of 27 is the thiocyanate anion.A similar study performed on 3-amino-2-methyl-8-(phenylmethoxy)imidazopyridine, labeled at the 3-position with carbon-13 (41) or carbon-14 (42), revealed that this compound, which has an antisecretory/cytoprotective profile comparable to that of 27, is also metabolized to thiocyanate anion, although this must occur via a different mechanism.The chemistry section includes a discussion of the potential sites of protonation of the pharmacologically similar 3-amino analogue 40 and the structurally related imidazopyrazine 67.Predictions based on charge density and protonation product stabilities are presented.That N1 is the site of protonation in these analogues has been definitively demonstrated by X-ray crystal structure analysis, which alsounequivocally established the assigned imidazopyrazine ring structure.
- Kaminski, James J.,Hilbert, James M.,Pramanik, B. N.,Solomon, Daniel M.,Conn, David J.,et al.
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p. 2031 - 2046
(2007/10/02)
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