Abstract：
:On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allylchlorpropamide 3 was, as expected, a potent inhibitor of hepatic AlDH in rats, as indicated by the 4-fold increase in the levels of ethanol-derived blood acetaldehyde relative to that elicited by chlorpropamide itself. Closely following in activity in decreasing order were N3-(n-propylcarbamoyl)uracil (7),N-(n-propylcarbamoyl)saccharin (6), and the S-(n-propylcarbamoyl) derivative (9) of benzyl mercaptan. However, two hydantoin derivatives, 5 and 8, were totally inactive in inhibiting AlDH in vivo. A prodrug of N1-ethylchlorpropamide, viz., its N3-trifluoroacetyl derivative (4b), was a good in vivo inhibitor of AlDH, mimicking the activity of the parent N1-ethylchlorpropamide. These results suggest that latent alkyl isocyanates are inhibitors of AlDH, giving further support to the hypothesis that the inhibition of AlDH in vivo by the hypoglycemic agent chlorpropamide may be due to the release of n-propyl isocyanate following metabolic bioactivation.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Nagasawa HT,Elberling JA,Goon DJ,Shirota FNdoi
10.1021/jm00050a018subject
Has Abstractpub_date
1994-11-25 00:00:00pages
4222-6issue
24eissn
0022-2623issn
1520-4804journal_volume
37pub_type
杂志文章abstract：:An essential step in the HIV life cycle is integration of the viral DNA into the host chromosome. This step is catalyzed by a 32-kDa viral enzyme HIV integrase (IN). HIV-1 IN is an important and validated target, and the drugs that selectively inhibit this enzyme, when used in combination with reverse transcriptase (R...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030378i
更新日期：2004-01-15 00:00:00
abstract：:A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00070a012
更新日期：1993-09-03 00:00:00
abstract：:2-Alkylchromen-4-one 6-O-sulfamates, a new class of potent steroid sulfatase (STS) inhibitors, were evaluated for their estrogenic potential. Structure-activity relationships for estrogenic activity were identified; however, no correlation with STS inhibition was found. Estrogenicity is favored by bulky side chains an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030926s
更新日期：2003-11-06 00:00:00
abstract：:Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00576
更新日期：2019-08-08 00:00:00
abstract：:In an intensive study of South American medicinal plants, herein we report the isolation, structure elucidation and biological activity of fourteen new and five known dihydro-beta-agarofuran sesquiterpenes from the leaves of Zinowiewia costaricensis (1-19). Their structures were determined by means of (1)H and (13)C N...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm058003f
更新日期：2005-06-30 00:00:00
abstract：:Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipoph...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301851v
更新日期：2013-03-28 00:00:00
abstract：:We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carrie...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200216q
更新日期：2011-07-28 00:00:00
abstract：:Cytochrome P450 aromatase catalyzes the conversion of androgen substrates into estrogens. Aromatase inhibitors (AIs) have been used as first-line drugs in the treatment of estrogen-dependent breast cancer in postmenopausal women. However, the search for new, more potent, and selective AIs still remains necessary to av...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2000689
更新日期：2011-06-23 00:00:00
abstract：:Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hamme...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00227a005
更新日期：1976-05-01 00:00:00
abstract：:Antitumor activity in mice was observed for the oxime of the previously reported ethyl [6-amino-4-[(1-methyl-2-phenyl-2-oxoethyl)amino]-5-nitropyridin -2-yl] carbamate (8) and several related compounds. These compounds are precursors of the active ethyl pyrido[3,4-b]pyrazin-7-ylcarbamates (e.g., 4), which are potent a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00098a014
更新日期：1992-10-02 00:00:00
abstract：:1-(Benzoyloxy), 1-(4-nitrobenzoyloxy), and 1-(3,5-dinitrobenzoyloxy) derivatives of 3-fluoro-, 3-chloro-, and 3-bromopropan-2-one were prepared by oxidation of the 1-benzoyloxy-3-halopropan-2-ols in turn prepared from the appropriate benzoyl chloride and 3-halo-1,2-propanediols, 1-Benzoyloxy-3-fluoropropan-2-one was a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00215a005
更新日期：1977-05-01 00:00:00
abstract：:A series of conformationally restricted congeners of pentamidine in which the flexible pentyl bridge of pentamidine was replaced by trans-1,2-bismethylenecyclopropyl, phenyl, pyridinyl, piperazinyl, homopiperazinyl, and piperidinyl groups were synthesized. The compounds were evaluated for trypanocidal activity in vitr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020375q
更新日期：2003-03-13 00:00:00
abstract：:Genetic mutations in the phosphatase PTPN11 (SHP2) are associated with childhood leukemias. These mutations cause hyperactivation of SHP2 due to the disruption of the autoinhibitory conformation. By targeting the activation-associated protein conformational change, we have identified an SHP2 inhibitor ( E)-1-(1-(5-(3-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00513
更新日期：2019-02-14 00:00:00
abstract：:Certain structural similarities between prostaglandins with close-packed side chains and the perhydrocyclopentanophenanthrene nucleus of steroids prompted the synthesis and biological evaluation of 6beta, 17 beta-dihydroxy-5alpha-androstane-2alpha-carboxylic acid (30), its 6-deoxy derivative 28, and the corresponding ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00235a002
更新日期：1975-01-01 00:00:00
abstract：:A three-dimensional quantitative structure-activity relationship using the comparative molecular field analysis (CoMFA) paradigm applied to 57 melatonin receptor ligands belonging to diverse structural families was performed. The compounds studied which have been synthesized previously and reported to be active at chi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960680+
更新日期：1997-02-28 00:00:00
abstract：:Nineteen derivatives of adenosine 5'-phosphate (AMP) bearing acylaminomethyl, acetoxy, or alkylaminomethyl substituents on the phosphate-ribose bridge (5' and O-5' positions) of AMP together with 2',3'-O-ethylidene, 2',3',-O-isopropylidene, and 2',3'-di-O-acetyl derivatives of AMP have been synthesized. Their substrat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00234a004
更新日期：1976-12-01 00:00:00
abstract：:Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated nonselective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00304
更新日期：2017-06-08 00:00:00
abstract：:To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some sigma receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH(3), CH(3)O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-py...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800965b
更新日期：2008-12-11 00:00:00
abstract：:Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention toward that go...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00898
更新日期：2020-03-12 00:00:00
abstract：:Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00030a012
更新日期：1994-02-18 00:00:00
abstract：:A common dichotomy exists in inhibitor design: should the compounds be designed to block the enzymes of animals in the preclinical studies or to inhibit the human enzyme? We report that a single mutation of Leu-337 in rat neuronal nitric oxide synthase (nNOS) to His makes the enzyme resemble human nNOS more than rat n...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900380j
更新日期：2009-07-23 00:00:00
abstract：:Interaction of 2-iodoaniline or 5-fluoro-2-iodoaniline with a range of arylsulfonyl chlorides affords sulfonamides that undergo Sonogashira couplings under thermal or microwave conditions with the alkyne 4-ethynyl-4-hydroxycyclohexa-2,5-dien-1-one followed by cyclization to 4-[1-(arylsulfonyl-1H-indol-2-yl)]-4-hydroxy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061163m
更新日期：2007-04-05 00:00:00
abstract：:New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00760
更新日期：2016-07-14 00:00:00
abstract：:Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tubercu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00432
更新日期：2016-06-23 00:00:00
abstract：:5'-(Bromoacetamido)-2',5'-dideoxyuridine (3) and derivatives (8, 10, 12, and 14) substituted at the 5-position with bromo, iodo, fluoro, and ethyl groups have been synthesized as potential inhibitors of enzymes that metabolize pyrimidine nucleosides. Also prepared were 2',5'-dideoxyuridine derivatives (4-6) substitute...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00388a031
更新日期：1987-05-01 00:00:00
abstract：:Prevalence of drug-resistant bacteria has emerged to be one of the greatest threats in the 21st century. Herein, we report the development of a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold. These molecules display good potency against a panel of multidrug-resista...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00640
更新日期：2016-09-08 00:00:00
abstract：:Glycosylation of 2-fluoroadenine with the appropriate protected thioglycoside derivatives, followed by deprotection and anomer separation, produced the alpha- and beta-anomers of 2',5'-dideoxy-2-fluoroadenosine (1), 2',5'-dideoxy-2,5'-difluoroadenosine (2), and 2'-deoxy-2-fluoroadenosine (3). These were examined as P-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0303599
更新日期：2004-02-26 00:00:00
abstract：:The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00743
更新日期：2018-09-13 00:00:00
abstract：:New acetamidines structurally related to N-(3-(aminomethyl)benzyl)acetamidine (1, W1400) were designed as inhibitors of inducible nitric oxide synthase (iNOS). Six compounds were found to be selective for iNOS over endothelial nitric oxide synthase (eNOS), and among them, the most active and selective compound was the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800846u
更新日期：2009-03-12 00:00:00
abstract：:The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400181k
更新日期：2013-05-09 00:00:00
