共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
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
3.
Ye P Kuhn C Juan M Sharma R Connolly B Alton G Liu H Stanton R Kablaoui NM 《Bioorganic & medicinal chemistry letters》2011,21(2):849-852
S6K1 (p70 S6 kinase-1) is thought to play a critical role in the development of obesity and insulin resistance, thus making it an attractive target in developing medicines for the treatment of these disorders. We describe a novel thiophene urea class of S6K inhibitors. The lead matter for the development of these inhibitors came from mining the literature for reports of weak off-target S6K activity. These optimized inhibitors exhibit good potency and excellent selectivity for S6K over a panel of 43 kinases. 相似文献
4.
Potent and selective cathepsin L inhibitors do not inhibit human osteoclast resorption in vitro 总被引:2,自引:0,他引:2
James IE Marquis RW Blake SM Hwang SM Gress CJ Ru Y Zembryki D Yamashita DS McQueney MS Tomaszek TA Oh HJ Gowen M Veber DF Lark MW 《The Journal of biological chemistry》2001,276(15):11507-11511
Cathepsins K and L are related cysteine proteases that have been proposed to play important roles in osteoclast-mediated bone resorption. To further examine the putative role of cathepsin L in bone resorption, we have evaluated selective and potent inhibitors of human cathepsin L and cathepsin K in an in vitro assay of human osteoclastic resorption and an in situ assay of osteoclast cathepsin activity. The potent selective cathepsin L inhibitors (K(i) = 0.0099, 0.034, and 0.27 nm) were inactive in both the in situ cytochemical assay (IC(50) > 1 micrometer) and the osteoclast-mediated bone resorption assay (IC(50) > 300 nm). Conversely, the cathepsin K selective inhibitor was potently active in both the cytochemical (IC(50) = 63 nm) and resorption (IC(50) = 71 nm) assays. A recently reported dipeptide aldehyde with activity against cathepsins L (K(i) = 0.052 nm) and K (K(i) = 1.57 nm) was also active in both assays (IC(50) = 110 and 115 nm, respectively) These data confirm that cathepsin K and not cathepsin L is the major protease responsible for human osteoclastic bone resorption. 相似文献
5.
Robichaud J Bayly C Oballa R Prasit P Mellon C Falgueyret JP Percival MD Wesolowski G Rodan SB 《Bioorganic & medicinal chemistry letters》2004,14(16):4291-4295
Prior reports from our laboratories have identified the nonpeptidic inhibitor 2 as a potent and selective Cathepsin K (Cat K) inhibitor. Modelling studies suggested that the introduction of a NH linker between the P3 aryl and P2 leucinamide moieties would allow the formation of a H-bond with the Gly66 residue of Cat K, hopefully increasing potency. Aniline 4 was thus synthesized and showed improved potency over its predecessor 2. Further modelling concluded that a 2-substituted five membered ring could more adequately place the P3 moiety of 4 into the S3 pocket of Cat K. The synthesis of the 2-substituted thiophene 5 confirmed this hypothesis by displaying a slight increase in potency against Cat K (>10-fold increase in potency vs 2) and a good selectivity profile against Cathepsins B, L, and S. This rationally designed inhibitor 5 also displayed increased potency in a functional bone resorption assay (10nM) versus 2 (95 nM). 相似文献
6.
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
7.
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
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.
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
10.
Arnold NJ Arnold R Beer D Bhalay G Collingwood SP Craig S Devereux N Dodds M Dunstan AR Fairhurst RA Farr D Fullerton JD Glen A Gomez S Haberthuer S Hatto JD Howes C Jones D Keller TH Leuenberger B Moser HE Muller I Naef R Nicklin PA Sandham DA Turner KL Tweed MF Watson SJ Zurini M 《Bioorganic & medicinal chemistry letters》2007,17(8):2376-2379
Inhibitors of PDE5 are useful therapeutic agents for treatment of erectile dysfunction. A series of novel xanthine derivatives has been identified as potent inhibitors of PDE5, with good levels of selectivity against other PDE isoforms, including PDE6. Studies in the dog indicate excellent oral bioavailability for compound 21. 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.
Hansen JD Grina J Newhouse B Welch M Topalov G Littman N Callejo M Gloor S Martinson M Laird E Brandhuber BJ Vigers G Morales T Woessner R Randolph N Lyssikatos J Olivero A 《Bioorganic & medicinal chemistry letters》2008,18(16):4692-4695
Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies. 相似文献
13.
Potent selective inhibitors of protein kinase C 总被引:21,自引:0,他引:21
P D Davis C H Hill E Keech G Lawton J S Nixon A D Sedgwick J Wadsworth D Westmacott S E Wilkinson 《FEBS letters》1989,259(1):61-63
A series of potent, selective inhibitors of protein kinase C has been derived from the structural lead provided by the microbial broth products, staurosporine and K252a. Our inhibitors block PCK in intact cells (platelets and T cells), and prevent the proliferation of mononuclear cells in response to interleukin 2 (IL2). 相似文献
14.
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
15.
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
16.
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
17.
Edmondson SD Mastracchio A Beconi M Colwell LF Habulihaz B He H Kumar S Leiting B Lyons KA Mao A Marsilio F Patel RA Wu JK Zhu L Thornberry NA Weber AE Parmee ER 《Bioorganic & medicinal chemistry letters》2004,14(20):5151-5155
In-house screening of the Merck sample collection identified proline derived homophenylalanine 3 as a DPP-IV inhibitor with modest potency (DPP-IV IC50=1.9 microM). Optimization of 3 led to compound 37, which is among the most potent and selective DPP-IV inhibitors discovered to date. 相似文献
18.
Reiter LA Freeman-Cook KD Jones CS Martinelli GJ Antipas AS Berliner MA Datta K Downs JT Eskra JD Forman MD Greer EM Guzman R Hardink JR Janat F Keene NF Laird ER Liras JL Lopresti-Morrow LL Mitchell PG Pandit J Robertson D Sperger D Vaughn-Bowser ML Waller DM Yocum SA 《Bioorganic & medicinal chemistry letters》2006,16(22):5822-5826
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50. 相似文献
19.
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
20.
Cherney RJ Mo R Meyer DT Wang L Yao W Wasserman ZR Liu RQ Covington MB Tortorella MD Arner EC Qian M Christ DD Trzaskos JM Newton RC Magolda RL Decicco CP 《Bioorganic & medicinal chemistry letters》2003,13(7):1297-1300
Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N-methanesulfonyl piperidine 23 and the N-trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC(50)=3nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14. 相似文献