title: Orally available pyridinylpyrimidine derivatives as novel RANKL-induced osteoclastogenesis inhibitors.
abstract: An HTS campaign led to the identification of 4-pyrroldino-2-(pyridin-2-yl)pyrimidine compound 1 as an RANKL-induced osteoclastogenesis inhibitor. The compound 1 showed high clearance values in microsomes, however. Modification of the pyrrolidino group to a benzylamino group improved human microsomal stability with a slight loss of in vitro activity. Substitution at the ortho position of the benzyl group ameliorated in vitro activity, and further fluorination of the benzyl group improved microsomal stability in rodents. Representative members of this series, compounds 20 and 23, exhibited efficacy in RANKL-induced osteopenic mice when administered orally at 0.3 mg/kg.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. junji.miyata@astellas.com
authors.forename: Junji
authors.initials: J
authors.lastname: Miyata
authors.forename: Chiyoshi
authors.initials: C
authors.lastname: Kasahara
authors.forename: Toru
authors.initials: T
authors.lastname: Asano
authors.forename: Shinji
authors.initials: S
authors.lastname: Ito
authors.forename: Norio
authors.initials: N
authors.lastname: Seki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kato
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Morikawa
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Nozaki
authors.forename: Kouji
authors.initials: K
authors.lastname: Nishimura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Akamatsu
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Taguchi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Abe
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohkubo
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053245:RANK Ligand / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; D011743:Pyrimidines; D053245:RANK Ligand