Journal of Medicinal Chemistry
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#1Giacomo Rossino (UNIPV: University of Pavia)H-Index: 4
#2Marta Rui (UNIPV: University of Pavia)H-Index: 9
Last. Bernhard Wünsch (WWU: University of Münster)H-Index: 32
view all 14 authors...
The sigma 1 receptor (S1R) is an enigmatic ligand-operated chaperone involved in many important biological processes, and its functions are not fully understood yet. Herein, we developed a novel series of bitopic S1R ligands as versatile tools to investigate binding processes, allosteric modulation, and the oligomerization mechanism. These molecules have been prepared in the enantiopure form and subjected to a preliminary biological evaluation, while in silico investigations helped to rationaliz...
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#1Zhuoxian Cao (MOE: Chinese Ministry of Education)H-Index: 2
#2Fen-Fen Yang (MOE: Chinese Ministry of Education)H-Index: 1
Last. Yongjun Li (MOE: Chinese Ministry of Education)H-Index: 10
view all 13 authors...
To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in se...
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The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted in silico using density functional theory. The capability of MECAM to function as an effective artificial siderophore in Escherichia coli was proven ...
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#1Pedro A. Valiente (U of T: University of Toronto)H-Index: 11
#2H. Wen (U of T: University of Toronto)
Last. Kyun-Do Kim (KRICT: Korea Research Institute of Chemical Technology)
view all 12 authors...
Blocking the association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) is an attractive therapeutic approach to prevent the virus from entering human cells. While antibodies and other modalities have been developed to this end, d-amino acid peptides offer unique advantages, including serum stability, low immunogenicity, and low cost of production. Here, we designed potent n...
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#1Cecilia C Ayala-Aguilera (Edin.: University of Edinburgh)
#2Teresa Valero (Edin.: University of Edinburgh)H-Index: 3
Last. Asier Unciti-Broceta (Edin.: University of Edinburgh)H-Index: 19
view all 6 authors...
The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kina...
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#1Youlong Fan (JNU: Jinan University)H-Index: 1
#2Si Hongfei (JNU: Jinan University)
Last. Shao Q. Yao (NUS: National University of Singapore)H-Index: 66
view all 14 authors...
The "inverse drug discovery" strategy is a potent means of exploring the cellular targets of latent electrophiles not typically used in medicinal chemistry. Cyclopropenone, a powerful electrophile, is generally used in bio-orthogonal reactions mediated by triarylphosphine or in photo-triggered cycloaddition reactions. Here, we have studied, for the first time, the proteome reactivity of cyclopropenones in live cells and discovered that the cyclopropenone warhead can specifically and efficiently ...
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#1Yanran Lu (OSU: Ohio State University)H-Index: 2
#2Sandip Vibhute (OSU: Ohio State University)H-Index: 5
Last. Anna Chen (OSU: Ohio State University)
view all 21 authors...
Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79. This molecule ...
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#1Tom D. Heightman (Astex)H-Index: 18
#2Valerio Berdini (Astex)H-Index: 2
Last. Lynsey Fazal (Astex)H-Index: 8
view all 35 authors...
Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimizatio...
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#1Rohan RejH-Index: 1
#2Changwei WangH-Index: 11
Last. Ruiting LiH-Index: 1
view all 18 authors...
Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC5...
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#1Huji TurdiH-Index: 3
#2Hannguang ChaoH-Index: 3
Last. Xiang-Yang YeH-Index: 6
view all 40 authors...
MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship aroun...
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