Abstract:
:Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based design, we incorporated an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand, and a 3,5-difluorophenylmethyl group as the P1-ligand. The resulting inhibitor 5 exhibited exceptional HIV-1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high-resolution X-ray crystal structure of the complex between inhibitor 5 and HIV-1 protease, which provides molecular insight into the unprecedented activity profiles observed.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Ghosh AK,Rao KV,Nyalapatla PR,Kovela S,Brindisi M,Osswald HL,Sekhara Reddy B,Agniswamy J,Wang YF,Aoki M,Hattori SI,Weber IT,Mitsuya Hdoi
10.1002/cmdc.201700824subject
Has Abstractpub_date
2018-04-23 00:00:00pages
803-815issue
8eissn
1860-7179issn
1860-7187journal_volume
13pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::Dihydropyrimidine-based compounds belong to the first discovered inhibitors of the human mitotic kinesin Eg5. Although they are used by many research groups as model compounds for chemical genetics, considerably less emphasis has been placed on the improvement of this type of inhibitor, with the exception of two recen...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000252
更新日期:2010-10-04 00:00:00
abstract::Serine- and metallo-β-lactamases present a threat to the clinical use of nearly all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo-β-lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β-lactamase activity and eff...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300350
更新日期:2013-12-01 00:00:00
abstract::First reported in the late 1930s and partly explained in 1970, the antibacterial activity of pectin remained almost ignored until the late 1990s. The concomitant emergence of research on natural antibacterials and new usages of pectin polysaccharides, including those in medicine widely researched in Russia, has led to...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000518
更新日期:2020-08-28 00:00:00
abstract::The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly in...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000456
更新日期:2011-03-07 00:00:00
abstract::Together with estrogen receptors ERα and ERβ, the G protein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators h...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700145
更新日期:2017-08-22 00:00:00
abstract::Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the m...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900329
更新日期:2019-07-17 00:00:00
abstract::The gold standard for the treatment of metastatic colorectal cancer consists of combination chemotherapy. Over time, however, the development of chemoresistant tumor clones leads to relapse. It may be possible to overcome oxaliplatin chemoresistance in colorectal cancer cells by exploiting a complex obtained from the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201400061
更新日期:2014-06-01 00:00:00
abstract::Despite significant advances made in the last decade in the understanding of molecular mechanisms of sepsis and in the development of clinically relevant therapies, sepsis remains the leading cause of mortality in intensive care units with increasing incidence worldwide. Toll-like receptor 4 (TLR4)-a transmembrane pat...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800505
更新日期:2018-11-06 00:00:00
abstract::We report the synthesis of trifluoromethylated metallocenes (M=Fe, Ru) and related metal-free compounds for comparison of their biological properties with the aim to establish structure-activity relationships toward the anti-proliferative activity of this compound class. All new compounds were comprehensively characte...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402001
更新日期:2014-06-01 00:00:00
abstract::A series of novel (R)/(S)-7-(3-alkoxyimino-2-aminomethyl-1-azetidinyl)fluoroquinolone derivatives were synthesized and evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that 12 of the target compounds generally show better activity (MIC: <0.008-0.5 μg mL(-1)) agains...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200210
更新日期:2012-07-01 00:00:00
abstract::There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62,000 compound library a...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900262
更新日期:2009-12-01 00:00:00
abstract::Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of thei...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800422
更新日期:2009-04-01 00:00:00
abstract::4H-1,2,4-Benzothiadiazine-1,1-dioxides with various substituents in positions 3, 5, and 7 were synthesized and tested as K(ATP) channel agonists in artificial cell systems (CHO cells transfected with SUR1/Kir6.2, and HEK 293 transfected with SUR2B/Kir6.1) as model systems for insulin-secreting pancreatic beta-cells an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900261
更新日期:2009-11-01 00:00:00
abstract::There is an urgent clinical need for imaging of α-synuclein (αSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of αSyn are rare. Diphenyl pyrazoles are known modulators of αSyn aggregation and thus bea...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900689
更新日期:2020-03-05 00:00:00
abstract::Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based on the 3-chlorobenzothiophene-2-hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds were prep...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800238
更新日期:2018-08-10 00:00:00
abstract::Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity relationship study of a small library ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800388
更新日期:2018-09-06 00:00:00
abstract::A library of 40,000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000083
更新日期:2010-07-05 00:00:00
abstract::Two libraries, each consisting of 48 16beta-aminopropyl estradiol derivatives, phenols and sulfamates, respectively, were synthesized by solid-phase parallel chemistry through a seven-step reaction sequence. Following the attachment of a C18-steroid sulfamate precursor on a trityl chloride resin, diversity elements we...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600071
更新日期:2006-11-01 00:00:00
abstract::The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200377
更新日期:2013-01-01 00:00:00
abstract::Drug metabolism, toxicity, and their interaction profiles are major issues in the drug-discovery and lead-optimization processes. The cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of marketed drugs. Therefore, the prediction of the binding affinity towards CYP2D6 an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000358
更新日期:2010-12-03 00:00:00
abstract::Given its role in the mediation of energy and glucose homeostasis, the G-protein-coupled bile acid receptor 1 (TGR5) is considered a potential target for the treatment of type 2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300144
更新日期:2013-07-01 00:00:00
abstract::We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moie...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000305
更新日期:2010-12-03 00:00:00
abstract::Racemic 2-{[1-(chloromethyl)-5-nitro-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}aminoethyl dihydrogen phosphate, a synthetic nitro derivative of the duocarmycins, is a hypoxia-selective prodrug active against radiation-resistant tumour cells at nontoxic doses in mice. An...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100271
更新日期:2011-10-04 00:00:00
abstract::Vascular endothelial growth factor receptor 2 (VEGFR2) has been proven to play a major role in the regulation of tumor angiogenesis. A series of novel glycyrrhetic acid derivatives were synthesized and evaluated for their VEGFR2 inhibitory activity as well as their antiproliferative properties against four cancer cell...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700271
更新日期:2017-07-06 00:00:00
abstract::From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and n...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200403
更新日期:2013-02-01 00:00:00
abstract::We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdraw...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600343
更新日期:2016-10-06 00:00:00
abstract::A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evalua...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300105
更新日期:2013-07-01 00:00:00
abstract::Unraveling the mechanisms involved in castration- and therapy-resistant prostate cancer has led to a renewed interest in androgen receptor (AR)-targeted therapeutics. Anti-androgens that block the activity of the AR therefore remain a valid therapeutic option. However, they must be more effective than, or display a di...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200549
更新日期:2013-04-01 00:00:00
abstract::In an approach to design drugs with higher affinity for π-π stacking and electrostatic interactions with targeted biomolecules, complexes of the type [{cis-Pt(A)2 (L)}2 -μ-{trans-1,4-dach}](NO3 )4 ((A)2 =(NH3 )2 or ethylenediamine (en), L=quinoline (quin) or benzothiazole (bztz), dach=trans-1,4-diaminocyclohexane) wer...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402052
更新日期:2014-06-01 00:00:00
abstract::Opening up ion channels: We synthesised a series of anthraquinone analogues, called the GoSlo-SR family. Their effects on bladder smooth muscle BK channels were examined and, as shown, shifted voltage dependent activation >-100 mV (at 10 μM). They were more efficacious than NS11021 and could provide a new scaffold for...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200321
更新日期:2012-10-01 00:00:00