Abstract：
:This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it important to consider the various different compounds separately, not necessarily as a class. The ketolide, telithromycin, was developed because of rising bacterial macrolide resistance but was withdrawn postapproval after visual disturbances, syncope, myasthenia gravis, and hepatotoxicity were noted. These diverse adverse effects could be attributed to inhibition of nicotinic acetylcholine receptors. Solithromycin, a later generation ketolide, was effective in treating bacterial pneumonia, but it was not approved by the U.S. Food and Drug Administration owing, in part, to its structural similarity to telithromycin. This Miniperspective describes that structurally similar macrolides/ketolides have clearly mechanistically distinct effects. Understanding these effects could help in developing and securing regulatory approval of a new macrolide/ketolide that is active against macrolide-resistant pathogenic bacteria.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Fernandes P,Pereira D,Watkins PB,Bertrand Ddoi
10.1021/acs.jmedchem.9b01159subject
Has Abstractpub_date
2020-06-25 00:00:00pages
6462-6473issue
12eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:Isolated hepatocytes carry out the N-demethylation of dansylamide at near linear rates for up to 8 h. This reaction was measured by following the release of tritium into water on hydroxylation of 3H-labeled methyl groups. The competitive inhibition of dansylamide by dansylated amino acids was studied in this system as...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00233a013
更新日期：1976-11-01 00:00:00
abstract：:Four 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepines were prepared and evaluated as central nervous system agents. All were active psychotropic agents as determined by animal screening tests. The most interesting compound, 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, showed dual activity as an ant...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00178a020
更新日期：1980-04-01 00:00:00
abstract：:The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 overexpression is thought to contribute to the development of cancer. We recently reported a series of (bis)guanidines and (bis)biguani...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100217a
更新日期：2010-07-22 00:00:00
abstract：:Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01621
更新日期：2020-04-23 00:00:00
abstract：:In this study, we developed an assignment-free approach for rapid identification of ligand-binding sites in target proteins by using NMR. With a sophisticated cell-free stable isotope-labeling procedure that introduces (15)N- or (13)C-labels to specific atoms of target proteins, this approach requires only a single se...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4014357
更新日期：2013-11-27 00:00:00
abstract：:A series of natural epimers of alpha-homonojirimycin and its N-alkylated derivatives have been prepared to investigate the contribution of the different chiral centers and conformation of the specificity and potency of inhibition of glycosidases. These epimers and N-alkylated derivatives are alpha-homonojirimycin (1),...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970836l
更新日期：1998-07-02 00:00:00
abstract：:Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701191z
更新日期：2008-04-24 00:00:00
abstract：:Peptidyl alpha-keto amides have been synthesized and tested as inhibitors of the cysteine protease calpain. A stereospecific synthesis was devised in which Cbz-dipeptidyl-alpha-hydroxy amides were oxidized with TEMPO/hypochlorite to the corresponding alpha-keto amides. This oxidation was accomplished in good yields an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00044a013
更新日期：1994-09-02 00:00:00
abstract：:Cyclin dependent kinases are a key family of kinases involved in cell cycle regulation and are an attractive target for cancer chemotherapy. The roles of four residues of the cyclin-dependent kinase active site in inhibitor selectivity were investigated by producing cyclin-dependent kinase 2 mutants bearing equivalent...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060216x
更新日期：2006-09-07 00:00:00
abstract：:A diverse 5000-compound library was synthesized from commercially available diamines and screened for activity against Mycobacterium tuberculosis in vitro, revealing 143 hits with minimum inhibitory concentration (MIC) equal to or less than 12.5 microM. New prospective scaffolds with antitubercular activity derived fr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050948+
更新日期：2006-06-01 00:00:00
abstract：:Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or ary...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950592+
更新日期：1996-02-16 00:00:00
abstract：:In pursuit of truncated glucagon analogues that can interact with the glucagon receptor with substantial binding affinity, 23 truncated glucagon analogues have been designed and synthesized. These truncated analogues consist of several fragments of glucagon with 11 or 12 amino acid residues (1-4), conformationally con...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000453e
更新日期：2001-04-26 00:00:00
abstract：:Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049355+
更新日期：2005-04-07 00:00:00
abstract：:A series of novel 3-arylethynyltriazolyl ribonucleosides were synthesized and assessed for their anticancer activity on the drug-resistant pancreatic cancer cell line MiaPaCa-2. Among them, one compound exhibited potent apoptosis-inducing properties and anticancer activity against the pancreatic cancer model MiaPaCa-2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900960v
更新日期：2009-10-08 00:00:00
abstract：:A series of 3,6-disubstituted pyridazino[4,3-c]isoquinolines were synthesized and tested for their ability to inhibit the binding of [3H]diazepam to rat brain receptors in vitro. Compounds bearing a phenyl, 4-methoxyphenyl, or methyl group at position 3 and a dialkylamino group at position 6 showed the highest affinit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00147a034
更新日期：1985-09-01 00:00:00
abstract：:Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying poten...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901378u
更新日期：2010-01-28 00:00:00
abstract：:Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5019719
更新日期：2015-02-26 00:00:00
abstract：:The possibility that catecholamines can be oxidized via aberrant pathways in vivo is open to question, but in vitro oxidation via aerobic manipulations is established. Assuming oxidation does occur, we have examined quantitatively the fast chemical reactions of the initial oxidation products, the o-quinones. The natur...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00223a008
更新日期：1976-01-01 00:00:00
abstract：:Several norindenoisoquinolines substituted with methoxy or methylenedioxy groups have been prepared and their anticancer properties evaluated in cancer cell cultures and in topoisomerase I inhibition assays. 2,3-Dimethoxy-8,9-methylenedioxy-11H-indeno[1,2-c]isoquinoline hydrochloride (14) is a strong topoisomerase I i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050076b
更新日期：2005-07-28 00:00:00
abstract：:Treatment of a protected 9-(5, 6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine derivative with silver nitrate and N-iodosuccinimide (NIS) and deprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Halogenation of 3-O-benzoyl-5,6-dideoxy-1, 2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-halo acetyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980163m
更新日期：1998-09-24 00:00:00
abstract：:Recent trends in drug discovery include methods to identify dual and triple activating drugs. This approach is being successfully employed in malaria, cancer, asthma, insulin resistance, etc. Molecular field analysis has been employed in correlating pharmacological data and field parameters. In this paper we introduce...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049383s
更新日期：2005-04-21 00:00:00
abstract：:Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01704
更新日期：2019-04-11 00:00:00
abstract：:A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701324c
更新日期：2008-03-27 00:00:00
abstract：:During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpho...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950956y
更新日期：1996-02-02 00:00:00
abstract：:HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00994
更新日期：2016-12-22 00:00:00
abstract：:Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01644
更新日期：2016-04-14 00:00:00
abstract：:A series of 2,2-diarylethylamine derivatives has been examined for potential antidepressant activity in the tetrabenazine (TBZ) test. Diethanolamine 4 (McN-4187) was one of the more potent compounds despite its polar alcohol functionalities [ED50 values of 15 mg/kg (exploratory activity) and 1.5 mg/kg (ptosis)]. Struc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00374a022
更新日期：1984-08-01 00:00:00
abstract：:In order to obtain agents with therapeutic indices superior to those of AZT, FLT, or D4T, several analogues of anti-HIV-1 nucleosides were synthesized. These include 2',3'-dideoxy-2',3' -difluoro-5-methyluridine (13), its arabino analogue 19, arabino-5-methylcytosine analogue 21, 3'-deoxy-2',3'-didehydro-2' -fluorothy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00109a017
更新日期：1991-05-01 00:00:00
abstract：:Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an enzyme explored in GDEPT. The more active acyclic 4-nitrobenzyl phosphoramide mustard (7) showed 167 500x selective cytotoxicity toward nitroreductase-expressing V79 cells with an IC(50) as low as 0.4 nM. This is ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm034133h
更新日期：2003-11-06 00:00:00
abstract：:We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9804127
更新日期：1998-12-03 00:00:00
