共查询到20条相似文献,搜索用时 15 毫秒
1.
Kerns JK Nie H Bondinell W Widdowson KL Yamashita DS Rahman A Podolin PL Carpenter DC Jin Q Riflade B Dong X Nevins N Keller PM Mitchell L Tomaszek T 《Bioorganic & medicinal chemistry letters》2011,21(15):4409-4415
A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P′ substituent. The cellular potency of selected analogs is also described. 相似文献
2.
Setti EL Davis D Janc JW Jeffery DA Cheung H Yu W 《Bioorganic & medicinal chemistry letters》2005,15(5):1529-1534
The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the 3,4-disubstituted azetidin-2-one warhead is reported. A high degree of potency and selectivity was achieved by introducing a basic nitrogen into the distal part of the P3 element of the molecule. Data from kinetic and mass spectrometry experiments are consistent with the interpretation that compounds of this series transiently acylate the sulfhydrile of cathepsin K. 相似文献
3.
Barrett DG Catalano JG Deaton DN Long ST Miller LR Tavares FX Wells-Knecht KJ Wright LL Zhou HQ 《Bioorganic & medicinal chemistry letters》2004,14(10):2543-2546
An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors. 相似文献
4.
Boros EE Deaton DN Hassell AM McFadyen RB Miller AB Miller LR Paulick MG Shewchuk LM Thompson JB Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2004,14(13):3425-3429
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM. 相似文献
5.
R W Marquis Y Ru D S Yamashita H J Oh J Yen S K Thompson T J Carr M A Levy T A Tomaszek C F Ijames W W Smith B Zhao C A Janson S S Abdel-Meguid K J D'Alessio M S McQueney D F Veber 《Bioorganic & medicinal chemistry》1999,7(4):581-588
Cathepsin K (EC 3.4.22.38) is a cysteine protease of the papain superfamily which is selectively expressed within the osteoclast. Several lines of evidence have pointed to the fact that this protease may play an important role in the degradation of the bone matrix. Potent and selective inhibitors of cathepsin K could be important therapeutic agents for the control of excessive bone resorption. Recently a series of peptide aldehydes have been shown to be potent inhibitors of cathepsin K. In an effort to design more selective and metabolically stable inhibitors of cathepsin K, a series of electronically attenuated alkoxymethylketones and thiomethylketones inhibitors have been synthesized. The X-ray co-crystal structure of one of these analogues in complex with cathepsin K shows the inhibitor binding in the primed side of the enzyme active site with a covalent interaction between the active site cysteine 25 and the carbonyl carbon of the inhibitor. 相似文献
6.
Barrett DG Catalano JG Deaton DN Hassell AM Long ST Miller AB Miller LR Shewchuk LM Wells-Knecht KJ Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2004,14(19):4897-4902
A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors. 相似文献
7.
Catalano JG Deaton DN Furfine ES Hassell AM McFadyen RB Miller AB Miller LR Shewchuk LM Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2004,14(1):275-278
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM. 相似文献
8.
Altmann E Aichholz R Betschart C Buhl T Green J Lattmann R Missbach M 《Bioorganic & medicinal chemistry letters》2006,16(9):2549-2554
A series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure 1 (Cbz-Leu-NH-CH2-CN, IC50 = 39 nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties. 相似文献
9.
Susana Ayesa Charlotta Lindquist Tatiana Agback Kurt Benkestock Björn Classon Ian Henderson Ellen Hewitt Katarina Jansson Anders Kallin Dave Sheppard Bertil Samuelsson 《Bioorganic & medicinal chemistry》2009,17(3):1307-1324
Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K. 相似文献
10.
Tavares FX Deaton DN Miller AB Miller LR Wright LL 《Bioorganic & medicinal chemistry letters》2005,15(17):3891-3895
Ketoheterocyclic inhibitors of cathepsin K have been disclosed. SAR of potency enhancing P2-P3 groups coupled with ketoheterocyclic warheads to provide cathepsin K inhibitors have been described. In addition, a novel route to access alpha-ketothiazoles using a key thioamide functionality has been disclosed. The mild method employed allows for the presence of diverse functional groups, such as amide and carbamate functionalities, commonly found in protease inhibitors that have peptidomimetic scaffolds. This new method should provide a quick entry into functionally diverse protease inhibitors. 相似文献
11.
Irie O Ehara T Iwasaki A Yokokawa F Sakaki J Hirao H Kanazawa T Teno N Horiuchi M Umemura I Gunji H Masuya K Hitomi Y Iwasaki G Nonomura K Tanabe K Fukaya H Kosaka T Snell CR Hallett A 《Bioorganic & medicinal chemistry letters》2008,18(14):3959-3962
Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats. 相似文献
12.
Léger S Bayly CI Black WC Desmarais S Falgueyret JP Massé F Percival MD Truchon JF 《Bioorganic & medicinal chemistry letters》2007,17(15):4328-4332
The nitrile warhead used in a series of cathepsin K inhibitors can be replaced by a less electrophilic primary amide. The accompanying loss of potency can be partially recovered by introducing a substituent alpha to the amide. The potency gain resulting from this addition is not achieved with the nitrile derivatives due to a different geometry of the cysteine adduct in the enzyme active site. This study led to the identification of the primary amide 2g, which is an inhibitory substrate, with an IC(50) of 10 nM against cathepsin K and excellent selectivity versus the other cathepsins. 相似文献
13.
Catalano JG Deaton DN Long ST McFadyen RB Miller LR Payne JA Wells-Knecht KJ Wright LL 《Bioorganic & medicinal chemistry letters》2004,14(3):719-722
A novel series of ketoamide-based inhibitors of cathepsin K has been identified. Modifications to P(2) and P(3) elements were crucial to enhancing inhibitory activity. Although not optimized, a selected inhibitor was effective in attenuating type I collagen hydrolysis in a surrogate assay of bone resorption. 相似文献
14.
Barrett DG Catalano JG Deaton DN Long ST McFadyen RB Miller AB Miller LR Wells-Knecht KJ Wright LL 《Bioorganic & medicinal chemistry letters》2005,15(9):2209-2213
Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor. 相似文献
15.
Barrett DG Boncek VM Catalano JG Deaton DN Hassell AM Jurgensen CH Long ST McFadyen RB Miller AB Miller LR Payne JA Ray JA Samano V Shewchuk LM Tavares FX Wells-Knecht KJ Willard DH Wright LL Zhou HQ 《Bioorganic & medicinal chemistry letters》2005,15(15):3540-3546
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model. 相似文献
16.
Cathepsin K is known to play an important role in bone resorption, and it has the P2 specificity for proline. Rat cathepsin K has 88% identity with the human enzyme. However, it has been reported that its enzymatic activity for a Cbz-Leu-Arg-MCA substrate is lower than that of human cathepsin K, and that the rat enzyme is not well inhibited by human cathepsin K inhibitors. For this study, we prepared recombinant enzyme to investigate the substrate specificity of rat cathepsin K. Cleavage experiments using the fragment of type I collagen and peptidic libraries demonstrated that rat cathepsin K preferentially hydrolyses the substrates at the P2 Hyp position. Comparison of the S2 site between rat and human cathepsin K sequences indicated that two S2 residues at Ser134 and Val160 in rat are varied to Ala and Leu, respectively, in the human enzyme. Cleavage experiments using two single mutants, S134A and V160L, and one double mutant, S134A/V160L, of rat cathepsin K showed that all the rat mutants lost the P2 Hyp specificity. The information obtained from our comparative studies on rat and human cathepsin K should make a significant impact on developing specific inhibitors of human cathepsin K since rat is usually used as test species. 相似文献
17.
Barrett DG Catalano JG Deaton DN Long ST McFadyen RB Miller AB Miller LR Samano V Tavares FX Wells-Knecht KJ Wright LL Zhou HQ 《Bioorganic & medicinal chemistry letters》2007,17(1):22-27
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone. 相似文献
18.
Yadav MR Shinde AK Chouhan BS Giridhar R Menard R 《Journal of enzyme inhibition and medicinal chemistry》2008,23(2):190-197
Cathepsins have been found to have important physiological roles. The implication of cathepsin L in various types of cancers is well established. In a search for selective cathepsin L inhibitors as anticancer agents, a series of 2-cyanoprrolidine peptidomimetics, carrying a nitrile group as warhead, were designed. Two series of compounds, one with a benzyl moiety and a second with an isobutyl moiety at P(2) position of the enzyme were synthesized. The synthesized compounds were evaluated for inhibitory activity against human cathepsin L and cathepsin B. Although, none of the compounds showed promising inhibitory activity, (E)N-{(S)1-[(S)2-cyano-1-pyrrolidinecarbonyl]-3-methylbutyl}-2,3-diphenylacrylamide (24) with an isobutyl moiety at P(2) was found to show selectivity as a cathepsin L inhibitor (Ki 5.3 microM for cathepsin L and Ki > 100 microM for cathepsin B). This compound could act as a new lead for the further development of improved inhibitors within this inhibitor type. 相似文献
19.
A novel series of 3,4-disubstituted azetidinones based inhibitors of the cysteine protease cathepsin K (Cat K) has been identified. Although not optimized, some of these compounds show at least 100-fold selectivity against other cathepsins. The use of cyclic moieties as P2 elements has proven to be crucial to achieve a high degree of selectivity. 相似文献
20.
Chatterjee AK Liu H Tully DC Guo J Epple R Russo R Williams J Roberts M Tuntland T Chang J Gordon P Hollenbeck T Tumanut C Li J Harris JL 《Bioorganic & medicinal chemistry letters》2007,17(10):2899-2903
Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of the P1 and P2 subsites resulted in the discovery of several potent and selective inhibitors of cathepsin S with good pharmacokinetic properties due to the elimination of saturated aliphatic P2 residues. 相似文献