共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
Tully DC Liu H Alper PB Chatterjee AK Epple R Roberts MJ Williams JA Nguyen KT Woodmansee DH Tumanut C Li J Spraggon G Chang J Tuntland T Harris JL Karanewsky DS 《Bioorganic & medicinal chemistry letters》2006,16(7):1975-1980
A series of N(alpha)-2-benzoxazolyl-alpha-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported. 相似文献
3.
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
4.
Barrett DG Catalano JG Deaton DN Hassell AM Long ST Miller AB Miller LR Ray JA Samano V Shewchuk LM Wells-Knecht KJ Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2006,16(6):1735-1739
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties. 相似文献
5.
Altmann E Green J Tintelnot-Blomley M 《Bioorganic & medicinal chemistry letters》2003,13(12):1997-2001
Modeling, synthesis and in vitro activities of a series of arylaminoethyl amide based inhibitors of the cysteine protease cathepsin K are described. 相似文献
6.
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
7.
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
8.
Teno N Miyake T Ehara T Irie O Sakaki J Ohmori O Gunji H Matsuura N Masuya K Hitomi Y Nonomura K Horiuchi M Gohda K Iwasaki A Umemura I Tada S Kometani M Iwasaki G Cowan-Jacob SW Missbach M Lattmann R Betschart C 《Bioorganic & medicinal chemistry letters》2007,17(22):6096-6100
Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20. 相似文献
9.
Shinozuka T Shimada K Matsui S Yamane T Ama M Fukuda T Taki M Takeda Y Otsuka E Yamato M Mochizuki S Ohhata K Naito S 《Bioorganic & medicinal chemistry》2006,14(20):6789-6806
A novel series of cathepsin K inhibitors derived from Novartis compound I is described. Optimization of the P1, P3, and P1' units led to the identification of 4-aminophenoxyacetic acid 24b with an IC(50) value of 4.8 nM, which possessed an excellent selectivity over other human cathepsins and good pharmacokinetic (PK) properties. Oral administration of compound 24b to ovariectomized (OVX) rats showed a trend toward an improvement of bone mineral density (BMD) in the femur bone. 相似文献
10.
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
11.
Barrett DG Deaton DN Hassell AM McFadyen RB Miller AB Miller LR Payne JA Shewchuk LM Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2005,15(12):3039-3043
Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model. 相似文献
12.
Teno N Irie O Miyake T Gohda K Horiuchi M Tada S Nonomura K Kometani M Iwasaki G Betschart C 《Bioorganic & medicinal chemistry letters》2008,18(8):2599-2603
Cyano pyrimidine acetylene and cyano pyrimidine t-amine, which belong to a new chemical class, were prepared and tested for inhibitory activities against cathepsin K and the highly homologous cathepsins L and S. The use of novel chemotypes in the development of cathepsin K inhibitors has been demonstrated by derivatives of compounds 1 and 8. 相似文献
13.
Palmer JT Hirschbein BL Cheung H McCarter J Janc JW Yu ZW Wesolowski G 《Bioorganic & medicinal chemistry letters》2006,16(11):2909-2914
We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P1, P2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis. 相似文献
14.
McGrath ME Sprengeler PA Hill CM Martichonok V Cheung H Somoza JR Palmer JT Janc JW 《Biochemistry》2003,42(51):15018-15028
Potent inhibitors of human cysteine proteases of the papain family have been made and assayed versus a number of relevant family members. We describe the synthesis of peptide alpha-ketoheterocyclic inhibitors that occupy binding subsites S1'-S3 of the cysteine protease substrate recognition cleft and that form a reversible covalent bond with the Cys 25 nucleophile. X-ray crystal structures of cathepsin K both unbound and complexed with inhibitors provide detailed information on protease/inhibitor interactions and suggestions for the design of tight-binding, selective molecules. 相似文献
15.
In order to better understand the structural and chemical features of human cathepsin K (CatK), which is an important cysteine protease in the pathogenesis of osteoporosis, the 3D-QSAR (CoMFA) studies were conducted on recently explored aldehyde compounds with known CatK inhibitory activities. The genetic algorithm of GOLD2.2 has been employed to position 59 aldehyde compounds into the active sites of CatK to determine the probable binding conformation. Good correlations between the predicted binding free energies and the experimental inhibitory activities suggested that the identified binding conformations of these potential inhibitors are reliable. The docking results also provided a reliable conformational alignment scheme for 3D-QSAR model. Based on the docking conformations, highly predictive comparative molecular field analysis (CoMFA) was performed with q2 value of 0.723. The predictive ability was validated by some compounds that were not included in the training set. Furthermore, the CoMFA model was mapped back to the binding sites of CatK, to get a better understanding of vital interactions between the aldehyde compounds and the protease. The CoMFA field distributions are in good agreement with the structural characteristics of the binding groove of the CatK, which suggested that the n-Bu in R4 position is the favor group substitute at P1 and moderate groups in R2 group are required on P2 substitute. In addition, 3D-QSAR results also demonstrated that aldehyde is an important pharmacophore because of electrostatic effect. These results, together with the good correlations between the inhibitory activities and the binding free energies predicted by GOLD2.2, demonstrated the power of combining docking/QSAR approach to explore the probable binding conformations of compounds at the active sites of the protein target, and further provided useful information in understanding the structural and chemical features of CatK in designing and finding new potential inhibitors. 相似文献
16.
Danielle K. Wiener Alice Lee-Dutra Scott Bembenek Steven Nguyen Robin L. Thurmond Siquan Sun Lars Karlsson Cheryl A. Grice Todd K. Jones James P. Edwards 《Bioorganic & medicinal chemistry letters》2010,20(7):2379-2382
A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity. 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.
Cathepsin K is the major enzyme responsible for the degradation of the protein matrix of bone and probably for the destruction of articular cartilage in rheumatoid arthritis joints. These processes occur mainly in the resorption lacuna and within the lysosomal compartment. Here, we have designed, synthesized, and evaluated new lysosomotropic (water-soluble) polymer-cathepsin K inhibitor conjugates. In particular, we characterized the relationship between conjugate structures and their activity to inhibit cathepsins K, B, L, and papain. A potent selective cathepsin K inhibitor, 1,5-bis(N-benzyloxycarbonylleucyl)carbohydrazide, was modified to 1-(N-benzyloxycarbonylleucyl)-5-(phenylalanylleucyl)carbohydrazide (I) to facilitate polymer conjugation. It was conjugated to the polymer chain termini of two water-soluble polymers [alpha-methoxy poly(ethylene glycol), abbreviated as mPEG-I; semitelechelic poly[N-(2-hydroxypropyl)methacrylamide], abbreviated as ST-PHPMA-I]. The conjugation of inhibitor I to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer side chains was accomplished via either a Gly-Gly spacer (PHPMA-GG-I) or with no spacer between I and the copolymer backbone (PHPMA-I). Kinetic analysis revealed that free inhibitor I possessed an apparent second-order rate constant against cathepsin K (k(obs)/[I] = 1.3 x 10(6) M(-1) s(-1)) similar to that of unmodified 1,5-bis(Cbz-Leu) carbohydrazide, while I conjugated to the chain termini of mPEG and ST-PHPMA-COOH had slightly lower values (about 5 x 10(5) M(-1) s(-1)). The k(obs)/[I] values for I attached to the side chains of HPMA copolymers (PHPMA-GG-I and PHPMA-I) were about 3 x 10(4) M(-1) s(-1). When tested against cathepsin L, inhibitor I and all its polymer conjugates produced k(obs)/[I] values 1-2 orders of magnitude less than those determined for cathepsin K, while for cathepsin B and papain, the values were 2-4 orders of magnitude lower. The ability of mPEG-I and ST-PHPMA-I to inhibit cathepsin K activity in synovial fibroblasts was also evaluated. Both polymer-bound inhibitors were internalized by endocytosis and were ultimately trafficked to the lysosomal compartment. ST-PHPMA-I was internalized faster than mPEG-I. The inhibitory activity in the synovial fibroblast assay correlated with the rate of internalization. 相似文献
19.
Deaton DN Hassell AM McFadyen RB Miller AB Miller LR Shewchuk LM Tavares FX Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2005,15(7):1815-1819
Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition. 相似文献
20.
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