Abstract：
:The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a number of neurodegenerative diseases, and overexpression of wild type p97 is observed in numerous cancers. Furthermore, p97 activity has been shown to be essential for the replication of certain viruses, including poliovirus, herpes simplex virus (HSV), cytomegalovirus (CMV), and influenza. Taken together, these observations highlight the potential for targeting p97 as a therapeutic approach in neurodegeneration, cancer, and certain infectious diseases. This Perspective reviews recent advances in the discovery of small molecule inhibitors of p97, their optimization and characterization, and therapeutic potential.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Huryn DM,Kornfilt DJP,Wipf Pdoi
10.1021/acs.jmedchem.9b01318subject
Has Abstractpub_date
2020-03-12 00:00:00pages
1892-1907issue
5eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章,评审abstract：:The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N(6)-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K(i) value of 0.66 microM. This result prompted an exploration of the structure-activity relationship of related derivatives, synth...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050221l
更新日期：2005-07-28 00:00:00
abstract：:As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N(6)-, 2-amino-N(6)-, and N(2)-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate ki...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000287a
更新日期：2000-11-02 00:00:00
abstract：:As part of our studies to develop novel retinoids with increased affinity and selectivity for the retinoid X receptor (RXR) subfamily, we have designed and synthesized a series of (E,E,E)-7-(1,2,3, 4-tetrahydroquinolin-6-yl)-7-alkyl-6-fluoro-3-methylhepta-2, 4, 6-trienoic acid derivatives. These tetrahydroquinolines, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980058c
更新日期：1998-08-13 00:00:00
abstract：:Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-PET radiotracer (1) or a fluorescence probe (2) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of 2 in biotin-receptor positive (BR+) canc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5019115
更新日期：2015-03-12 00:00:00
abstract：:A series of 2-(2-nitrobenzoyl)cyclohexane-1,3-dione analogues (1-9) were designed, synthesized, and evaluated for inhibition of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), a key enzyme involved in the catabolism of tyrosine which catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. The correlations ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010568y
更新日期：2002-05-23 00:00:00
abstract：:A series of 1-R-5-alkoxy-3H-1,4-benzodiazepin-2(1H)-ones was prepared and evaluated for central nervous system depressant activity. Several of these compounds, in particular, 7-chloro-5-ethoxy-1-methyl-3H-1,4-benzodiazepin-2(1H)-one (2), gave a profile and activity level similar to diazepam when measured in mice. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00217a019
更新日期：1977-07-01 00:00:00
abstract：:Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a defin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00843
更新日期：2019-05-23 00:00:00
abstract：:Building on the previously and successfully applied hypothesis that stereochemical complication in the proximity of the critical cationic head of a cholinergic agonist would result in subtype selective compounds, we synthesized a series of chiral derivatives of furmethide and 5-methylfurmethide, with the aim of obtain...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800145d
更新日期：2008-07-10 00:00:00
abstract：:Learning and memory deficits in Alzheimer's disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (M...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300353r
更新日期：2012-08-09 00:00:00
abstract：:We report the syntheses of first-generation derivatives of isothiazolopyridones and their in vitro evaluation as antibacterial agents. These compounds, containing a novel heterocyclic nucleus composed of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the quinolizin-4-one), were prepared using a sequen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm051066d
更新日期：2006-01-12 00:00:00
abstract：:C-terminally truncated fragments of human alpha-calcitonin gene-related peptide (h-alpha-CGRP) were tested for their ability to stimulate amylase secretion from pancreatic acinar cells and relax precontracted mesenteric arteries. h-alpha-CGRP, h-alpha-CGRP (1-36), h-alpha-CGRP (1-35), and h-alpha-CGRP (1-34) were made...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00069a012
更新日期：1993-08-20 00:00:00
abstract：:The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060435i
更新日期：2006-08-10 00:00:00
abstract：:Three types of brassinosteroid analogues with perfluoroalkylated side chains were synthesized by using alkene cross-metathesis of a brassinosteroid derivative bearing a terminal alkene moiety with different (perfluoroalkyl)propenes. The presence of the double bonds in the cross-metathesis products allowed a facile one...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900495f
更新日期：2009-09-24 00:00:00
abstract：:Neutrophil serine proteases, proteinase 3 (PR3) and human neutrophil elastase (HNE), are considered as targets for chronic inflammatory diseases. Despite sharing high sequence similarity, the two enzymes have different substrate specificities and functions. While a plethora of HNE inhibitors exist, PR3 specific inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500782s
更新日期：2014-11-26 00:00:00
abstract：:Two complete and two partial structure-activity relationship scans of the active fragment of human growth hormone-releasing hormone, [Nle27]-hGHRH(1-29)-NH2, have identified potent agonists in vitro. Single-point replacement of each amino acid by alanine led to the identification of [Ala8]-, [Ala9]-, [Ala15]- (Felix e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970618s
更新日期：1998-02-26 00:00:00
abstract：:Derivatives of N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide bearing a wide variety of different groups at the 5-position (and for comparative purposes at the 7-position) have been prepared, and their physicochemical properties and biological activities have been determined. Although both 5- and 7-substitut...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00387a013
更新日期：1987-04-01 00:00:00
abstract：:The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha2beta3gamma2 and alpha3beta3gamma2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801652d
更新日期：2009-04-09 00:00:00
abstract：:omega-Acryloyl anionic surfactants, whose polar heads are derived from amino acids, have been telomerized to prepare polyanions of a predetermined molecular weight. The main goal of this study was to verify whether the antiviral activity is influenced by the degree of polymerization of the polyanions. The oligomeric p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960493b
更新日期：1997-01-31 00:00:00
abstract：:S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules wit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00928
更新日期：2015-12-10 00:00:00
abstract：:A conformationally defined retinoic acid analog (1) which contains a dimethylene bridge to maintain the 6-s-trans orientation for two terminal double bonds in the polyene chain was synthesized. A Reformatsky reaction was utilized to extend the polyene chain of the starting enone, which provided exclusively the 9Z-conf...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00052a009
更新日期：1994-12-23 00:00:00
abstract：:In an analogy to the potent catechol dopamine D1 agonists dihydrexidine (1) and dinapsoline (2), benzo rings were fused onto the structures of the dopamine D2-selective agonists quinelorane (3) and quinpirole (4). Each of the phenyl ring-substituted derivatives had significant affinity for D2 receptors, albeit somewha...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9804533
更新日期：1999-03-11 00:00:00
abstract：:A series of N-alkyl-3-[m-(trifluoromethyl)phenyl]-5-hydroxy-2-pyrrolidinones and N-alkyl-3-(trifluoromethyl)-cinnamamides were prepared and screened in a series of tests designed to detect potential sleep inducers. The more active members of the series were evaluated for their ability to induce sleep in Cebus monkeys....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00379a007
更新日期：1985-01-01 00:00:00
abstract：:Much has been discussed about the proper physicochemical properties (e.g., molecular weight, hydrophobicity, etc.) that should be considered when utilizing fragment leads in drug design. However, little has been reported as to what emphasis, if any, should be placed on the potency of the resulting fragment leads. In t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060511h
更新日期：2006-11-30 00:00:00
abstract：:The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited and incurable neurodegenerative disorders primarily afflicting the pediatric population. Current treatment regimens offer only symptomatic relief and do not target the underlying cause of the disease. Although the underlying pathophysiology that drives...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.5b01020
更新日期：2016-05-26 00:00:00
abstract：:In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400438k
更新日期：2013-09-12 00:00:00
abstract：:The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailabilit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0304515
更新日期：2004-05-06 00:00:00
abstract：:The in vitro antineoplastic activity of many phosphorus-containing (e.g., phosphocholines) and non-phosphorus-containing (e.g., quaternary ammonium salts) ether lipids has been evaluated in the HL-60 promyelocytic cell line. These compounds are analogues of ET-18-OMe (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphochol...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00066a011
更新日期：1993-07-09 00:00:00
abstract：:A series of 4- and 5-[2,3-dihydro-6,7-bis[[(N-alkylcarbamoyl)oxy]methyl]-1H-pyrrol izin-5- yl]-2-halopyridinium iodides were synthesized. The rates of hydrolysis of the alpha-halopyridinium salts to the corresponding pyridones, and the reactivities of the carbamate moieties were studied as a function of pH, buffer com...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00168a021
更新日期：1990-06-01 00:00:00
abstract：:PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive struct...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01674
更新日期：2018-02-08 00:00:00
abstract：:The discovery of selective endothelin (ET) receptor antagonists will facilitate identification of the physiological and pathological roles for ET and its isopeptides. Structure-activity studies of the C-terminal hexapeptide of ET have been carried out to elucidate those amino acids important for receptor binding and a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00070a001
更新日期：1993-09-03 00:00:00
