Abstract:
:A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Hirata K,Kotoku M,Seki N,Maeba T,Maeda K,Hirashima S,Sakai T,Obika S,Hori A,Hase Y,Yamaguchi T,Katsuda Y,Hata T,Miyagawa N,Arita K,Nomura Y,Asahina K,Aratsu Y,Kamada M,Adachi T,Noguchi M,Doi S,Crowe P,Bradledoi
10.1021/acsmedchemlett.5b00253subject
Has Abstractpub_date
2015-11-04 00:00:00pages
23-7issue
1issn
1948-5875journal_volume
7pub_type
杂志文章abstract::Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-a...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
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更新日期:2019-10-30 00:00:00
abstract::With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...
journal_title:ACS medicinal chemistry letters
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abstract::The Hu family of RNA-binding proteins plays a crucial role in post-transcriptional processes; indeed, Hu-RNA complexes are involved in various dysfunctions (i.e., inflammation, neurodegeneration, and cancer) and have been recently proposed as promising therapeutic targets. Intrigued by this concept, our research effor...
journal_title:ACS medicinal chemistry letters
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abstract::GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclizati...
journal_title:ACS medicinal chemistry letters
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doi:10.1021/ml1000855
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abstract::B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein-protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 tha...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
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abstract::The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5'-deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC50 values against the most se...
journal_title:ACS medicinal chemistry letters
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abstract::A new category of cationic meso-thiophenium porphyrins are introduced as possible alternatives to the popular meso-pyridinium porphyrins. Combinations of cationic porphyrins bearing meso-2-methylthiophenium and meso-4-hydroxyphenyl moieties T2(OH)2M (A2B2 type) and T(OH)3M (AB3 type) along with their zinc(II) complexe...
journal_title:ACS medicinal chemistry letters
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abstract::A novel modulator of sodium ion currents was synthesized in 6 steps from a protected dihydroxypyrrolidine nitrone, via 1,3-dipolar cycloaddition reaction with acrylamide. Sodium ion currents in B50 cells were evaluated in comparison to saxitoxin and tetrodotoxin, and revealed an IC(50) of 15.7 muM. The new compound sh...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
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abstract::ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/...
journal_title:ACS medicinal chemistry letters
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journal_title:ACS medicinal chemistry letters
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journal_title:ACS medicinal chemistry letters
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journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
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abstract::[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...
journal_title:ACS medicinal chemistry letters
pub_type: 已发布勘误
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journal_title:ACS medicinal chemistry letters
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abstract::Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding and maturation of client proteins that are associated with all ten hallmarks of cancer. Hsp90 N-terminal pan inhibitors have experienced unfavorable results in clinical trials due to induction of the heat shock response (HSR), a...
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journal_title:ACS medicinal chemistry letters
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journal_title:ACS medicinal chemistry letters
pub_type: 社论
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journal_title:ACS medicinal chemistry letters
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journal_title:ACS medicinal chemistry letters
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更新日期:2015-01-28 00:00:00