Effect of cathepsin K inhibitors on bone resorption.
On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.
Teno
Naoki
N
Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan. naoki.teno@novartis.com
Masuya
Keiichi
K
Ehara
Takeru
T
Kosaka
Takatoshi
T
Miyake
Takahiro
T
Irie
Osamu
O
Hitomi
Yuko
Y
Matsuura
Naoko
N
Umemura
Ichiro
I
Iwasaki
Genji
G
Fukaya
Hiroaki
H
Toriyama
Kazuhiro
K
Uchiyama
Noriko
N
Nonomura
Kazuhiko
K
Sugiyama
Ikuo
I
Kometani
Motohiko
M
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D024042:Collagen Type I / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics*; D000882:Haplorhini; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds; D014018:Tissue Distribution
D024042:Collagen Type I; D015853:Cysteine Proteinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013141:Spiro Compounds; C527741:pyrrolopyrimidine; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat