共查询到20条相似文献,搜索用时 31 毫秒
1.
Miller JF Furfine ES Hanlon MH Hazen RJ Ray JA Robinson L Samano V Spaltenstein A 《Bioorganic & medicinal chemistry letters》2004,14(4):959-963
A novel series of P1' chain-extended arylsufonamides was synthesized and evaluated for wild-type HIV protease inhibitory activity and in vitro antiviral activity against wild type virus and two protease inhibitor-resistant mutant viruses. All of the compounds showed dramatic increases in enzyme activity as compared to the currently marketed HIV protease inhibitors amprenavir, indinavir, and nelfinavir. In addition, significant improvements in antiviral potencies against wild type and the two mutant viruses were also realized. 相似文献
2.
Miller JF Andrews CW Brieger M Furfine ES Hale MR Hanlon MH Hazen RJ Kaldor I McLean EW Reynolds D Sammond DM Spaltenstein A Tung R Turner EM Xu RX Sherrill RG 《Bioorganic & medicinal chemistry letters》2006,16(7):1788-1794
A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385. 相似文献
3.
Mimoto T Nojima S Terashima K Takaku H Shintani M Hayashi H 《Bioorganic & medicinal chemistry》2008,16(3):1299-1308
A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs. 相似文献
4.
5.
Design and synthesis of highly potent HIV protease inhibitors with activity against resistant virus 总被引:1,自引:0,他引:1
Lu Z Raghavan S Bohn J Charest M Stahlhut MW Rutkowski CA Simcoe AL Olsen DB Schleif WA Carella A Gabryelski L Jin L Lin JH Emini E Chapman K Tata JR 《Bioorganic & medicinal chemistry letters》2003,13(10):1821-1824
A series of highly potent HIV protease inhibitors have been designed and synthesized. These compounds are active against various clinical viral isolates as well as wild-type virus. The synthesis and biological activity of these HIV protease inhibitors are discussed. 相似文献
6.
Stranix BR Lavallée JF Sévigny G Yelle J Perron V LeBerre N Herbart D Wu JJ 《Bioorganic & medicinal chemistry letters》2006,16(13):3459-3462
A series of lysine sulfonamide analogues bearing Nepsilon-acyl aromatic amino acids were synthesized using an efficient synthetic route. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type and multiple-protease inhibitor-resistant HIV viruses. 相似文献
7.
Giang Le Nick Vandegraaff David I. Rhodes Eric D. Jones Jonathan A.V. Coates Long Lu Xinming Li Changjiang Yu Xiao Feng John J. Deadman 《Bioorganic & medicinal chemistry letters》2010,20(17):5013-5018
A series of novel HIV integrase inhibitors active against rategravir resistant strains are reported. Initial SAR studies revealed that activities against wild-type virus were successfully maintained at single digit nanomolar level with a wide range of substitutions. However, inclusion of nitrogen-based cyclic substitutions was crucial for achieving potency against mutant viruses. Several compounds with excellent activities against wild-type virus as well as against the viruses with the mutations Q148H/G140S or N155H/E92Q were reported. 相似文献
8.
Stranix BR Sauvé G Bouzide A Coté A Sévigny G Yelle J Perron V 《Bioorganic & medicinal chemistry letters》2004,14(15):3971-3974
A series of lysine sulfonamide analogues bearing a Nepsilon-benzylic ureas was synthesized using both solution-phase and solid-phase approaches. A novel synthetic route of Nalpha-(alkyl)-Nalpha-(sulfonamides)lysinol using alpha-amino-caprolactam was developed. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type HIV virus. 相似文献
9.
Mimoto T Terashima K Nojima S Takaku H Nakayama M Shintani M Yamaoka T Hayashi H 《Bioorganic & medicinal chemistry》2004,12(1):281-293
A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted all-phenylnorstatine [APNS: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were designed and synthesized. From the structure-metabolism relationship of this type of HIV protease inhibitors, the compounds having para substitution of the phenyl ring of Apns and/or 2,6-disubstitution of the P2' benzylamine were found to be able to avoid the P2 phenol glucuronidation that occurs with SM-319777 (formerly named JE-2147, KNI-764); one of the main metabolic pathways of SM-319777. These new analogues, such as SM-322377, had more desirable pharmacokinetic profiles and more potent antiviral activity against not only wild type HIV-1 but also the multi-drug-resistant HIV-1 than SM-319777. 相似文献
10.
Jiang T Kuhen KL Wolff K Yin H Bieza K Caldwell J Bursulaya B Tuntland T Zhang K Karanewsky D He Y 《Bioorganic & medicinal chemistry letters》2006,16(8):2109-2112
A series of heterocycle-containing oxindoles was synthesized and their HIV antiviral activities were assessed. Some of these analogs exhibited potent inhibitory activities against both wild-type virus and a number of drug-resistant mutant viruses. In addition, oxindole 9z also showed promising pharmacokinetics. 相似文献
11.
Human immunodeficiency virus (HIV) protease is a well-established drug target in HIV chemotherapy. However, continuously increasing resistance towards approved drugs inevitably requires the development of new inhibitors preferably showing no susceptibility against resistant HIV protease strains. Recently, symmetric pyrrolidine-3,4-bis-N-benzyl-sulfonamides have been developed as a new class of HIV-1 protease inhibitors. The most promising candidate exhibited a Ki of 74 nM towards a wild-type protease. Herein, we report the influence of the active-site mutations Ile50Val and Ile84Val on these inhibitors by structural and kinetic analysis. Although the Ile50Val mutation leads to a significant decrease in affinity for all compounds in this series, they retain or even show increased affinity towards the important Ile84Val mutation. By detailed analysis of the crystal structures of two representatives in complex with wild-type and mutant proteases, we were able to elucidate the structural basis of this phenomenon. 相似文献
12.
13.
Lu Z Bohn J Rano T Rutkowski CA Simcoe AL Olsen DB Schleif WA Carella A Gabryelski L Jin L Lin JH Emini E Chapman K Tata JR 《Bioorganic & medicinal chemistry letters》2005,15(23):5311-5314
Efforts directed to identifying potent HIV protease inhibitors (PI) have yielded a class of compounds that are not only very active against wild-type (NL4-3) HIV virus but also very potent against a panel of PI-resistant viral isolates. Chemistry and biology are described. 相似文献
14.
15.
Raghavan S Lu Z Beeson T Chapman KT Schleif WA Olsen DB Stahlhut M Rutkowski CA Gabryelski L Emini E Tata JR 《Bioorganic & medicinal chemistry letters》2007,17(19):5432-5436
A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described. 相似文献
16.
Eissenstat M Guerassina T Gulnik S Afonina E Silva AM Ludtke D Yokoe H Yu B Erickson J 《Bioorganic & medicinal chemistry letters》2012,22(15):5078-5083
We have designed and synthesized a series of HIV protease inhibitors (PIs) with enamino-oxindole substituents optimized to interact with the S2' subsite of the HIV protease binding pocket. Several of these inhibitors have sub-nanomolar K(i) and antiviral IC(50) in the low nM range against WT HIV and against a panel of multi-drug resistant (MDR) strains. 相似文献
17.
Yunjeong Kim Scott Lovell Kok-Chuan Tiew Sivakoteswara Rao Mandadapu Kevin R. Alliston Kevin P. Battaile William C. Groutas Kyeong-Ok Chang 《Journal of virology》2012,86(21):11754-11762
Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro. 相似文献
18.
The dimeric aspartyl protease of HIV has been the subject of intense research for almost a decade. Knowledge of the substrate specificity and catalytic mechanism of this enzyme initially guided the development of several potent peptidomimetic small molecule inhibitors. More recently, the solution of the HIV protease structure led to the structure-based design of improved peptidomimetic and non-peptidomimetic antiviral compounds. Despite the qualified success of these inhibitors, the high mutation rate associated with RNA viruses continues to hamper the long-term clinical efficacy of HIV protease inhibitors. The dimeric nature of the viral protease has been conducive to the investigation of dominant-negative inhibitors of the enzyme. Some of these inhibitors are defective protease monomers that interact with functional monomers to form inactive protease heterodimers. An advantage of macromolecular inhibitors as compared to small-molecule inhibitors is the increased surface area of interaction between the inhibitor and the target gene product. Point mutations that preserve enzyme activity but confer resistance to small-molecule inhibitors are less likely to have an adverse effect on macromolecular interactions. The use of efficient retrovirus vectors has facilitated the delivery of these macromolecular inhibitors to primary human lymphocytes. The vector-transduced cells were less susceptible to HIV infection in vitro, and showed similar levels of protection compared to other macromolecular inhibitors of HIV replication, such as RevM10. These preliminary results encourage the further development of dominant-negative HIV protease inhibitors as a gene therapy-based antiviral strategy. 相似文献
19.
《Bioorganic & medicinal chemistry》2020,28(13):115541
The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir. 相似文献