Abstract:
:The discovery and characterization of two classes of kappa opioid receptor agonists that are biased for G protein over βarrestin signaling are described.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Bohn LM,Aubé Jdoi
10.1021/acsmedchemlett.7b00224subject
Has Abstractpub_date
2017-07-05 00:00:00pages
694-700issue
7issn
1948-5875journal_volume
8pub_type
杂志文章abstract::APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/P...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500389m
更新日期:2014-11-04 00:00:00
abstract::Despite the perceived stability of the C-F bond, chemical instability and drug-metabolizing enzymes can lead to its cleavage. The resulting release of fluoride and formation of certain metabolites may cause safety issues and warrant the medicinal chemists' attention. ...
journal_title:ACS medicinal chemistry letters
pub_type: 社论
doi:10.1021/acsmedchemlett.9b00235
更新日期:2019-06-20 00:00:00
abstract::Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinas...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400206q
更新日期:2013-08-12 00:00:00
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
pub_type: 杂志文章
doi:10.1021/ml1001807
更新日期:2010-10-20 00:00:00
abstract::Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00181
更新日期:2019-07-02 00:00:00
abstract::A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated i...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200250t
更新日期:2011-11-21 00:00:00
abstract::A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1' aromatic portion and a d-proline residue bearing the zinc-binding group. The ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300446a
更新日期:2013-05-14 00:00:00
abstract::ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse antic...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00289
更新日期:2018-07-25 00:00:00
abstract::The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00403
更新日期:2016-02-12 00:00:00
abstract::Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400533y
更新日期:2014-01-17 00:00:00
abstract::Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diamin...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml3000879
更新日期:2012-06-06 00:00:00
abstract::Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (9a-f) or hippuric (11a,b) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00094
更新日期:2020-03-18 00:00:00
abstract::Mitragyna speciosa, also known as kratom, has the potential meet the need for pain medications that lack the addictiveness and overdose risk of classical opioid analgesics, such as morphine. This need is urgent because opioid addiction and overdose deaths have risen throughout diverse segments of U.S. society. Some op...
journal_title:ACS medicinal chemistry letters
pub_type: 社论
doi:10.1021/acsmedchemlett.7b00298
更新日期:2017-08-08 00:00:00
abstract::The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substitute...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00462
更新日期:2020-10-13 00:00:00
abstract::This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml1002508
更新日期:2010-12-02 00:00:00
abstract::Structure-based design methods commonly used in medicinal chemistry rely on a three-dimensional representation of the receptor. However, few crystal structures are solved in comparison with the huge number of pharmaceutical targets. This often renders homology models the only information available. It is particularly ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100288q
更新日期:2011-02-11 00:00:00
abstract::Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00586
更新日期:2020-01-09 00:00:00
abstract::GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00444
更新日期:2018-12-03 00:00:00
abstract::A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be dis...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00040
更新日期:2020-05-18 00:00:00
abstract::Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathw...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5003234
更新日期:2014-10-29 00:00:00
abstract::The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TD...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00369
更新日期:2018-11-04 00:00:00
abstract::We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represe...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100060m
更新日期:2010-05-26 00:00:00
abstract::Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carbox...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5003629
更新日期:2014-11-11 00:00:00
abstract::Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains el...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00172
更新日期:2020-06-02 00:00:00
abstract::Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinson's and Alzheimer's. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this clas...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00287
更新日期:2015-08-31 00:00:00
abstract::A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood poo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml1002458
更新日期:2011-07-22 00:00:00
abstract::Carbazoles represent a family of tricyclic compounds that widely appeared in nature. Numerous studies have revealed a diverse array of bioactivity associated with this scaffold. In the present study, a novel and highly efficient methodology for preparing 1,3-dihydroxy-2-carboxycarbazole from indole-3-acetic acid and M...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00158
更新日期:2015-07-10 00:00:00
abstract::Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysio...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00097
更新日期:2019-05-08 00:00:00
abstract::[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300216t
更新日期:2012-09-25 00:00:00
abstract::We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystalli...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00420
更新日期:2019-11-19 00:00:00