Effect of Cathepsin K Inhibitors on Bone Resorption

Abstract

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.

Orally Bioavailable Cathepsin K Inhibitors with Pyrrolopyrimidine Scaffold

“…A number of related cathepsin K inhibitors with warhead group that covalently bind to active site Cys25 of cathepsin K have been identified [25][26][27][28][29][30][31][32][33][34]. The Merck group has recently reported that the electrophilicity and reactivity of nitrile-containing inhibitors, in three different chemical classes, has an impact on the reversibility of the enzymeinhibitor complex [38].…”

“…Novel inhibitors possessing the P3 group derived from the spiro-hydantoin structure were prepared and the inhibitory potency for cathepsin K was evaluated as shown in Tables 6 and 7 [29]. Replacement of the P3 moiety with the reversed analogue of 41 resulted in the retention of potency and no substantial change in the selectivity against cathepsins L and S (41 vs 42).…”

“…The concept is based on the information on substrate specificity [23] and a warhead (nitrile group) [24], which binds to a thiol group of the active center of cathepsin K. This war head, which was used in early research phase on cathepsin K inhibitors in Novartis, was successfully utilized in the design for the first non-peptidic cathepsin K inhibitors [25][26][27][28][29]. Identification of the nitrile group as the warhead also had a significant impact on the cathepsin K inhibitors developed by other research institutes [30][31][32][33][34].…”

“…This review will focus on the significant progress reported in the literatures from 2004 onwards, which marks the first disclosure of non-peptidic cathepsin K inhibitors having purine, pyrimidine or pyrrolopyrimidine scaffold (A -E) [25][26][27][28][29] as depicted in Fig. 1, starting from the identification of a low-nanomolar high-throughput screening hit, 1 [25] (Fig 2).…”

Novel type of plasmin inhibitors: Providing insight into P4 moiety and alternative scaffold to pyrrolopyrimidine

“…Unlike the aldehyde inhibitors, a variety of inhibitors possessing a nitrile moiety as the warhead functions as mild electron deficient center and the functional group were introduced to many enzyme inihibitors. [12][13][14][15] In this area, we exerted effort to develop totally new chemotype plasmin inhibitors. On the basis of information on substrate specificity of plasmin, non-peptidic and peptidic plasmin inhibitors having the nitrile moiety as the warhead were first designed and prepared.…”