title: Studies on disease-modifying antirheumatic drugs. III. Bone resorption inhibitory effects of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate (TAK-603) and related compounds.
abstract: In the course of our studies aimed at obtaining new drugs for treatment of bone and joint diseases, chemical modification of the potent bone resorption inhibitors justicidins, was performed and various naphthalene lactones, quinoline lactones and quinoline derivatives bearing an azole moiety at the side chain were prepared. Their inhibitory effects on bone resorption were evaluated by Raisz's method, and several compounds, including ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmeth yl)quinoline -3-carboxylate (6c, TAK-603), were found to have activities comparable with or superior to the justicidins. The 4-(3-isopropoxy-4-methoxy)-phenyl derivative (6d), in particular, displayed a marked increase in potency. TAK-603 and compound 6d were very effective in preventing osteoclast formation and bone resorption by mature osteoclasts. Further, TAK-603 was shown to be effective in preventing bone loss in ovariectomized mice.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Baba
authors.forename: T
authors.initials: T
authors.lastname: Oda
authors.forename: S
authors.initials: S
authors.lastname: Taketomi
authors.forename: K
authors.initials: K
authors.lastname: Notoya
authors.forename: A
authors.initials: A
authors.lastname: Nishimura
authors.forename: H
authors.initials: H
authors.lastname: Makino
authors.forename: T
authors.initials: T
authors.lastname: Sohda
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control*; D001842:Bone and Bones / Q000473:pathology / Q000648:ultrastructure; D002132:Calcium Radioisotopes; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D010010:Osteoclasts / Q000187:drug effects / Q000648:ultrastructure; D010052:Ovariectomy; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D018501:Antirheumatic Agents; D002132:Calcium Radioisotopes; D011804:Quinolines; D014230:Triazoles; C104411:TAK 603