Abstract:
:A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed significant activity in these models when administered either systemically or topically. Protein chimeras were constructed to indicate compounds from the series bound in the S5 region of the channel, and a computational docking model was used to propose a binding mode for example compounds.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Pryde DC,Marron BE,West CW,Reister S,Amato G,Yoger K,Antonio B,Padilla K,Cox PJ,Turner J,Warmus JS,Swain NA,Omoto K,Mahoney JH,Gerlach ACdoi
10.1021/acsmedchemlett.7b00140subject
Has Abstractpub_date
2017-05-18 00:00:00pages
666-671issue
6issn
1948-5875journal_volume
8pub_type
杂志文章abstract::Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were selected as putative Notch inhibitors. The evaluation of the antiproliferative effect combined with the inhibition of Notch1 expression in KOPTK1 cell line identified compound 18, featuring a tetrahydronaphthalene-b...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00608
更新日期:2019-02-26 00:00:00
abstract::Re(I) tricarbonyl polypyridine-based complexes are particularly attractive metal complexes in the field of inorganic chemical biology due to their luminescent properties, ease of conjugation to targeting biomolecules, and the possibility to prepare their "hot" (99m)Tc analogues for radioimaging. In this study, we prep...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500158w
更新日期:2014-05-15 00:00:00
abstract::A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200032v
更新日期:2011-04-04 00:00:00
abstract::Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was di...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00504
更新日期:2017-04-12 00:00:00
abstract::A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust ph...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500440u
更新日期:2015-05-07 00:00:00
abstract::A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00247
更新日期:2015-07-20 00:00:00
abstract::In this work, we present an investigation into the physical properties of a unique class of aromatic boronic acids, the benzoxaboroles. Using spectrophotometric methods, the ionization constants of a family of substituted benzoxaboroles are determined. Heterocyclic ring modifications are examined to determine their ef...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200215j
更新日期:2011-10-19 00:00:00
abstract::Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to fur...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00300
更新日期:2018-10-01 00:00:00
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::The signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for oncology drug development. We identified a N-[2-(1,3,4-oxadiazolyl)]-4-quinolinecarboxamide derivative, STX-0119, as a novel STAT3 dimerization inhibitor by a virtual screen using a customized versio...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml1000273
更新日期:2010-07-13 00:00:00
abstract::Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no SAR studies have been conducted on the noviose appendage, which represents the rate-l...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100070r
更新日期:2010-07-13 00:00:00
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...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00100
更新日期:2020-06-11 00:00:00
abstract::Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide-amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, whi...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500494j
更新日期:2015-01-28 00:00:00
abstract::The solution behavior of auranofin, Et3PAuCl and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward re...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00162
更新日期:2017-09-06 00:00:00
abstract::Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's M...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00558
更新日期:2019-02-07 00:00:00
abstract::EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functio...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00358
更新日期:2017-10-02 00:00:00
abstract::A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carbo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300396r
更新日期:2013-01-04 00:00:00
abstract::Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and b...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5002097
更新日期:2014-07-16 00:00:00
abstract::[This corrects the article DOI: 10.1021/acsmedchemlett.8b00507.]. ...
journal_title:ACS medicinal chemistry letters
pub_type: 已发布勘误
doi:10.1021/acsmedchemlett.9b00316
更新日期:2019-08-06 00:00:00
abstract::Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel f...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00380
更新日期:2018-10-31 00:00:00
abstract::An original design and synthesis of fluorescent ligands for melatonin receptor studies is presented and consists in the fusion of the endogenous ligand with the fluorescent BODIPY core. Probes I-IV show high affinities for MT1 and MT2 melatonin receptors and exhibit fluorescence properties compatible with cell observa...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml4004155
更新日期:2013-11-20 00:00:00
abstract::Fluorescent biosensors constitute potent tools for probing biomolecules in their natural environment and for visualizing dynamic processes in complex biological samples, living cells, and organisms. They are well suited for highlighting molecular alterations associated with pathological disorders, thereby offering mea...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400472e
更新日期:2013-12-18 00:00:00
abstract::A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold w...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00269
更新日期:2020-07-09 00:00:00
abstract::A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4'-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (compo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400203d
更新日期:2013-07-12 00:00:00
abstract::Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar r...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml4004556
更新日期:2014-01-10 00:00:00
abstract::Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structu...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00319
更新日期:2020-09-10 00:00:00
abstract::PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining a...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00306
更新日期:2016-10-10 00:00:00
abstract::A new pseudopeptide epoxide inhibitor, designed for irreversible binding to HIV protease (HIV-PR), has been synthesized and characterized in solution and in the solid state. However, the crystal structure of the complex obtained by inhibitor-enzyme cocrystallization revealed that a minor isomer, with inverted configur...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500092e
更新日期:2014-07-14 00:00:00
abstract::C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00385
更新日期:2015-10-31 00:00:00
abstract::Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not ind...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5004475
更新日期:2014-12-12 00:00:00