Abstract:
:HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Jiang Y,Andrews SW,Condroski KR,Buckman B,Serebryany V,Wenglowsky S,Kennedy AL,Madduru MR,Wang B,Lyon M,Doherty GA,Woodard BT,Lemieux C,Geck Do M,Zhang H,Ballard J,Vigers G,Brandhuber BJ,Stengel P,Josey JA,Beigelmdoi
10.1021/jm400164csubject
Has Abstractpub_date
2014-03-13 00:00:00pages
1753-69issue
5eissn
0022-2623issn
1520-4804journal_volume
57pub_type
杂志文章abstract::Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unatt...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0305523
更新日期:2004-05-06 00:00:00
abstract::The cyclopropyl compounds (Z)- and (E)-2-amino-2,3-methano-4-phosphonobutanoic acid, 5 and 6, respectively, were prepared as constrained analogues of 2-amino-4-phosphonobutanoic acid (AP4), a selective glutamate receptor ligand. A Horner-Emmons reaction of trimethyl N-(benzyloxycarbonyl)phosphonoglycinate with 2-(diet...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00109a023
更新日期:1991-05-01 00:00:00
abstract::Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compoun...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501285x
更新日期:2015-01-22 00:00:00
abstract::In this work, we introduce a four-step scoring and filtering procedure, furnishing target specific virtual screening (TS-VS), which serves to minimize false positives resulting from conformational artifacts of the docking process and is optimized to converge on novel chemotypes of estrogen receptor alpha (ERalpha). As...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0700262
更新日期:2007-11-01 00:00:00
abstract::Identifying local similarities in binding sites from distant proteins is a major hurdle to rational drug design. We herewith present a novel method, borrowed from computer vision, adapted to mine fragment subpockets and compare them to whole ligand-binding sites. Pockets are represented by pharmacophore-annotated poin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c00422
更新日期:2020-07-09 00:00:00
abstract::A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00397
更新日期:2016-07-28 00:00:00
abstract::The preparation of stable complexes between the N7-[2-(2-pyridyl)ethyl] and N7-(2-piperazinylethyl) derivatives of mitomycin C and metal ions such as Cu(II), Zn(II), and Pt(II) was accomplished. Mitomycin C did not form stable complexes, but it rearranged to a mitosene capable of complex formation. Some of these compl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00151a023
更新日期:1986-01-01 00:00:00
abstract::While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improv...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00033
更新日期:2017-03-09 00:00:00
abstract::The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, res...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00389
更新日期:2016-06-23 00:00:00
abstract::The 2'-chloro derivatives of etoposide and 4 beta-(arylamino)-4'-O-demethylpodophyllotoxins have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results showed that none of the compoun...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00083a009
更新日期:1992-03-06 00:00:00
abstract::Basic derivatives of 6,7-dihydroindolo[1,7-ab][1]benzazepine and 6H-indolo[7,1-cd][1,5]benzoxazepine incorporating the imipramine basic side chain were synthesized and screened for antidepressant activity in mice. With few exceptions, the compounds unsubstituted at C-2 antagonized reserpine-induced ptosis and hypother...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00224a003
更新日期:1976-02-01 00:00:00
abstract::New fluorinated 2-aryl-benzothiazoles, -benzoxazoles, and -chromen-4-ones have been synthesized and their activity against MCF-7 and MDA 468 breast cancer cell lines compared with the potent antitumor benzothiazole 5. Analogues such as 9a, b and 12a, d yielded submicromolar GI50 values in both cell lines; however, non...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800418z
更新日期:2008-08-28 00:00:00
abstract::Three novel C-4 aziridine-bearing paclitaxel analogs, 3-5, have been synthesized during the course of our continuing effort at C-4 modification. The key step in the synthesis is the aziridine ring formation at the C-4 position via an intramolecular Mitsunobu reaction. The syntheses and the biological evaluation of the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00012a029
更新日期:1995-06-09 00:00:00
abstract::An enzymatically activated liposome-based drug-delivery concept involving masked antitumor ether lipids (AELs) has been investigated. This concept takes advantage of the cytotoxic properties of AEL drugs as well as the membrane permeability enhancing properties of these molecules, which can lead to enhanced drug diffu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm031029r
更新日期:2004-03-25 00:00:00
abstract::In order to study the preferential involvement of mu or delta receptors in the analgesic effects of enkephalins, several peptides which selectively interact with these two kinds of receptors in peripheral organs were synthesized. The inhibitory potency on the electrically stimulated mouse vas deferens (delta receptors...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00142a002
更新日期:1981-10-01 00:00:00
abstract::The clinical antileukemic drug amsacrine and analogues are thought to exert their biological activity by binding tightly but reversibly to DNA, with the acridine chromophore intercalated and the anilino group making additional binding contact in the minor groove of the double helix. In this binding model the steric en...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00365a014
更新日期:1983-11-01 00:00:00
abstract::A series of 1-[[[5-(substituted phenyl)-2-oxazolyl]methylene]amino]- 2,4-imidazolidinediones (6a-t) was synthesized, and the compounds were evaluated for direct skeletal muscle inhibition in the pithed rat gastrocnemius muscle preparation. The correctness of structural assignment of the new series was verified by alte...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00385a006
更新日期:1987-02-01 00:00:00
abstract::5-Oxo-ETE is the most powerful eosinophil chemoattractant among lipid mediators. Eosinophil infiltration into the lungs of asthmatics may be responsible for the late phase of inflammatory asthma. We have designed and synthesized a 5-oxo-ETE receptor antagonist, the purpose of which is to prevent eosinophil migration t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400480j
更新日期:2013-05-09 00:00:00
abstract::We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]6), 4-[(18)F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]7), and 4-[(18)F]fluoropropoxy-N-[4-[6-(isopro...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm201590g
更新日期:2012-03-08 00:00:00
abstract::As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N(6)-, 2-amino-N(6)-, and N(2)-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate ki...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000287a
更新日期:2000-11-02 00:00:00
abstract::In the present work, we have designed and synthesized a series of arachidonic acid derivatives of general structure I which have been characterized as highly potent and selective inhibitors of anandamide transporter (IC(50) = 24-0.8 microM, K(i) > 1000-5000 nM for CB(1) and CB(2) cannabinoid receptors and vanilloid VR...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm015545y
更新日期:2001-12-20 00:00:00
abstract::Anthrax lethal factor (LF) is a critical virulence factor in the pathogenesis of anthrax. A structure-activity relationship (SAR) of potential lethal factor inhibitors (LFi) is presented in which the zinc-binding group (ZBG), linker, and backbone moieties for a series of hydroxypyrone-based compounds were systematical...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8013212
更新日期:2009-02-26 00:00:00
abstract::A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00026a011
更新日期:1995-12-22 00:00:00
abstract::Sepsis is characterized by a systemic inflammatory response syndrome. Derivatives of indole have been reported to exhibit diverse biological activities. This study reports on the design and synthesis of a new series of indole-2-carboxamide derivatives, which are screened for their anti-inflammatory activities in RAW 2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b02006
更新日期:2016-05-26 00:00:00
abstract::A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones wa...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00051a005
更新日期:1994-12-09 00:00:00
abstract::The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)isoquinoline derivatives with different levels of hydrogenation and varying substitution of the phenyl ring is reported. These compou...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980434t
更新日期:1999-09-09 00:00:00
abstract::We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9804127
更新日期:1998-12-03 00:00:00
abstract::The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501207r
更新日期:2014-12-26 00:00:00
abstract::A theoretically rigorous and computationally tractable methodology for the prediction of the free energies of binding of protein-ligand complexes is presented. The method formulated involves developing molecular dynamics trajectories of the enzyme, the inhibitor, and the complex, followed by a free energy component an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010175z
更新日期:2001-12-06 00:00:00
abstract::A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineopla...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000045a
更新日期:2000-07-13 00:00:00