title: A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy.
abstract: In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human.
authors: Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kashiwagihrt@chugai-pharm.co.jp
authors: Hirotaka
authors: H
authors: Kashiwagi
authors: Yoshiyuki
authors: Y
authors: Ono
authors: Masateru
authors: M
authors: Ohta
authors: Susumu
authors: S
authors: Itoh
authors: Fumihiko
authors: F
authors: Ichikawa
authors: Suguru
authors: S
authors: Harada
authors: Satoshi
authors: S
authors: Takeda
authors: Nobuo
authors: N
authors: Sekiguchi
authors: Masaki
authors: M
authors: Ishigai
authors: Tadakatsu
authors: T
authors: Takahashi
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D002460:Cell Line; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015675:Osteocalcin / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; C552205:CH 5036249; D011725:Pyridines; D018167:Receptors, Calcitriol; D015675:Osteocalcin; D002762:Cholecalciferol