Abstract：
:Transient receptor potential canonical (TRPC) channels are highly homologous, nonselective cation channels that form many homo- and heterotetrameric channels. These channels are highly abundant in the brain and kidney and have been implicated in numerous diseases, such as depression, addiction, and chronic kidney disease, among others. Historically, there have been very few selective modulators of the TRPC family in order to fully understand their role in disease despite their physiological significance. However, that has changed recently and there has been a significant increase in interest in this family of channels which has led to the emergence of selective tool compounds, and even preclinical drug candidates, over the past few years. This review will cover these new advancements in the discovery of TRPC modulators and the emergence of newly reported structural information which will undoubtedly lead to even greater advancements.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Sharma S,Hopkins CRdoi
10.1021/acs.jmedchem.8b01954subject
Has Abstractpub_date
2019-09-12 00:00:00pages
7589-7602issue
17eissn
0022-2623issn
1520-4804journal_volume
62pub_type
杂志文章,评审abstract：:For disease network intervention, up-regulating enzyme activities is equally as important as down-regulating activities. However, the design of enzyme activators presents a challenging route for drug discovery. Previous studies have suggested that activating 15-lipoxygenase (15-LOX) is a promising strategy to interven...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01011
更新日期：2016-05-12 00:00:00
abstract：:We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral admini...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,随机对照试验
doi：10.1021/jm901802n
更新日期：2010-02-25 00:00:00
abstract：:An application of the neural network to quantitative structure-activity relationship (QSAR) analysis has been studied. The new method was compared with the linear multiregression analysis in various ways. It was found that the neural network can be a potential tool in the routine work of QSAR analysis. The mathematica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm00171a037
更新日期：1990-09-01 00:00:00
abstract：:9-acridinyl derivatives of 1,6-hexanediamine, 1,8-octanediamine, bis(3-aminopropyl)amine, N,N'-bis(3-amino-propyl)piperazine, and N-ethyl-1,6-hexanediamine in the form of their hydrochlorides were prepared in high yields and converted into potential hetero bis DNA intercalating diacridines. The corresponding potential...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00364a028
更新日期：1983-10-01 00:00:00
abstract：:Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200694q
更新日期：2011-10-13 00:00:00
abstract：:The sequence and configuration of amino acids in the cytostatic cyclic tetrapeptide WF-3161 are established as cyclo(L-Leu-L-Pip-L-Aoe-D-Phe) where Pip = pipecolic acid and Aoe = 2-amino-8-oxo-9,10-epoxydecanoic acid. In chloroform, WF-3161 adopts a conformation with a possible gamma-turn between Leu NH and Aoe C = O ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00161a046
更新日期：1986-11-01 00:00:00
abstract：:Pharmacophore, two-dimensional (2D), and three-dimensional (3D) quantitative structure-activity relationship (QSAR) modeling techniques were used to develop and test models capable of rationalizing and predicting human UDP-glucuronosyltransferase 1A4 (UGT1A4) substrate selectivity and binding affinity (as K(m,app)). T...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020397c
更新日期：2003-04-24 00:00:00
abstract：:Conjugation of pleuromutilin is an attractive strategy for the development of novel antibiotics and the fight against multiresistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01328
更新日期：2020-12-24 00:00:00
abstract：:Production of the Gag-Pol polyprotein in human immunodeficiency virus (HIV) requires a -1 ribosomal frameshift, which is directed by a highly conserved RNA stem-loop. Building on our discovery of a set of disulfide-containing peptides that bind this RNA, we describe medicinal chemistry efforts designed to begin to und...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100231t
更新日期：2010-08-26 00:00:00
abstract：:A variety of N-(phenylsulfonyl)-N-phenylglycines 5, N-(phenylsulfonyl)-2-phenylglycines 6, and N-(phenylsulfonyl)anthranilic acids 7 were prepared as analogues of the N-(phenylsulfonyl)glycine 1 aldose reductase inhibitors. In the rat lens assay, several derivatives of 5 display greater inhibitory activity than the co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00121a027
更新日期：1989-01-01 00:00:00
abstract：:Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introdu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01729
更新日期：2019-02-28 00:00:00
abstract：:Antagonism of mercaptopropionic acid (MPA) induced convulsions, reflecting a GABAergic mechanism, was observed in a series of 1-aryl-3-(aminoalkylidene)oxindoles. Optimal MPA antagonism was associated with 3-halo, 3-alkyl, and/or 4-alkoxy substituents in the pendant aryl ring and with (dimethylamino)methylene, 1-(dime...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00122a025
更新日期：1989-02-01 00:00:00
abstract：:This paper describes the chemical synthesis and CCK-B and CCK-A receptor binding affinities of a series of compounds in which the central amide bond of the CCK-B "dipeptoid" ligand tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,S*)]-[2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]carb amate (4) ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00086a017
更新日期：1992-04-17 00:00:00
abstract：:A new and extensive set of 4-(6-iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine (IMPY) derivatives was synthesized and assayed for affinity toward human Abeta plaques. 6-Ethylthio- (12h), 6-cyano- (12e), 6-nitro- (12f), and 6-p-methoxybenzylthio- (15d) analogues were discovered to have high affinity (KI < 10...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0702231
更新日期：2007-09-20 00:00:00
abstract：:We report the esterification of the carboxyl groups of the cyclic peptide toxins nodularin-R and microcystin-LA to produce stable diacetoxymethyl and dipropionyloxymethyl ester derivatives. The derivatives had no activity but were reactivated upon esterase treatment. When injected into cells, the acyloxymethyl moietie...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900502e
更新日期：2009-09-24 00:00:00
abstract：:The discovery of the (acryloylaryloxy)acetic acids as a new class of potent diuretics prompted the investigation of related bicyclic compounds. Annelated analogues of the parent series, the (2-alkyl- and 2,2-dialkyl-1-oxo-5-indanyloxy)acetic acids, were the subjects of this study. Those compounds, unlike the monocycli...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00221a010
更新日期：1977-11-01 00:00:00
abstract：:We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling. The complex of TNKS2 with the potent inhibitor XAV939 provides insights into the molecular basis of the strong interaction and sugg...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100249w
更新日期：2010-07-22 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801546k
更新日期：2009-05-14 00:00:00
abstract：:A series of 3-(alkoxymethyl)-alpha-(N-substituted aminomethyl)-4-hydroxybenzyl alcohols was synthesized as potential bronchodilators. The ability to prevent effects against histamine-induced bronchoconstriction in guinea pigs was studied to determine their bronchodilating activity. Introduction of a methoxymethyl grou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00189a012
更新日期：1979-03-01 00:00:00
abstract：:The synthesis and testing of potential multisubstrate inhibitors of tyrosine-specific protein kinases are described. One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-[4-(fluorosulfonyl)benzoyl]adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics. The resulting mult...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00117a015
更新日期：1988-09-01 00:00:00
abstract：:Reaction of nitric oxide (NO) with L-proline in methanolic sodium methoxide yields a diazeniumdiolate product, C5H7N3O4Na2.CH3OH (PROLI/NO), that can be stabilized in basic solution but that dissociates to proline (1 mol) and NO (2 mol) with a half-life of only 1.8 s at pH 7.4 and 37 degrees C. This kinetic behavior h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960616s
更新日期：1996-10-25 00:00:00
abstract：:The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01322
更新日期：2018-02-08 00:00:00
abstract：:The binding constants of 15 phenothiazine derivatives to bovine serum albumin were obtained by a circular dichroic probe technique; The lipophilicity of the drugs, measured by a reversed-phase thin-layer technique using oleyl alcohol and methanol-water mixtures as the solvents, is expressed as RMw. The binding constan...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00213a022
更新日期：1977-03-01 00:00:00
abstract：:Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00275
更新日期：2017-12-28 00:00:00
abstract：:The nature of the carbonyl and nitrogen substituents of hydroxamic acids has a major influence on the biological profile of these compounds. Hydroxamates with small groups such as methyl appended to the carbonyl and relatively large nitrogen substituents generally have longer duration in vivo, produce greater plasma c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00118a016
更新日期：1988-10-01 00:00:00
abstract：:The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0211218
更新日期：2003-05-22 00:00:00
abstract：:In an effort to determine the stereochemical requirements for pharmacological activity among the series of nonclassical cannabinoids synthesized at Pfizer, we have studied the conformational properties of the parent bicyclic analog CP-47,497. For this study, we have used a combination of solution NMR and theoretical c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00036a006
更新日期：1994-05-13 00:00:00
abstract：:A series of eight C5-substituted analogues of (+-)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (1) have been prepared by the directed lithiation-alkylation (and acylation) of its (+-)-N-tert-butylformamidinyl derivative 2 followed by formamidine solvolysis. An additional 10 analogues were prepared by elaborati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00165a029
更新日期：1990-03-01 00:00:00
abstract：:Over 25 selected naphthalenesulfonic acid derivatives were evaluated for their inhibitory effect on two different functional domains of the HIV-1 reverse transcriptase (RT), namely the ribonuclease H and DNA polymerase activities. Most of the analogues were found to be either specific toward the DNA polymerase activit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00042a004
更新日期：1994-08-05 00:00:00
abstract：:A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500818a
更新日期：2014-08-14 00:00:00
