Abstract：
:Certain L1210-active bis(guanylhydrazones) have structural and biological properties in common with the DNA minor groove binding, antileukemic, bisquaternary ammonium heterocycles. Monitoring of the DNA binding of the bis(guanylhydrazones), by fluorimetric quantitation of drug displacement of DNA-bound ethidium, shows that, like the bisquaternary salts, these agents bind more strongly to poly[d(A-T)] than poly[d(G-C)]. The drug concentrations necessary to inhibit L1210 DNA-dependent DNA polymerase in vitro by 50% (IC50) are linearly related to measures of drug-DNA binding with no preference for a particular primary sequence of DNA being evident. Mammalian toxicity of the bis(guanylhydrazones) is effectively modeled by a regression equation containing binomial terms in Rm values, used as a measure of agent lipophilic-hydrophilic balance, and the logarithms of the IC50 values.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Denny WA,Cain BFdoi
10.1021/jm00196a016subject
Has Abstractpub_date
1979-10-01 00:00:00pages
1234-8issue
10eissn
0022-2623issn
1520-4804journal_volume
22pub_type
杂志文章abstract：:New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis ( Mtb) inosine 5'-monophosphate dehydrogenase 2 ( MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guani...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01839
更新日期：2018-06-14 00:00:00
abstract：:A close analogue of the antileukemic agent 5,8-dideaza-N10 propargylfolic acid (2) was synthesized by replacing the propargyl moiety of 2 with a cyanomethyl group. This compound, N10-(cyanomethyl)-5,8-dideazafolic acid (3), was evaluated for its antifolate and antitumor activities in several biological test systems. A...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00358a030
更新日期：1983-04-01 00:00:00
abstract：:We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antid...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00099a018
更新日期：1992-10-16 00:00:00
abstract：:A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones wa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00051a005
更新日期：1994-12-09 00:00:00
abstract：:Network theory provides one of the most potent analysis tools for the study of complex systems. In this paper, we illustrate the network-based perspective in drug research and how it is coherent with the new paradigm of drug discovery. We first present data sources from which networks are built, then show some example...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01989
更新日期：2020-08-27 00:00:00
abstract：:Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0509997
更新日期：2006-02-09 00:00:00
abstract：:A variety of N-(aminoalkanoyl)-S-acylcysteamine and N,N'-bis(aminoalkanoyl)cystamine salt derivatives were synthesized. Toxicity and radioprotective activity (as the dose reduction factor DRF) were determined in vivo on mice and compared to WR 2721 and S-acetylcysteamine hydrochloride. One of the most interesting comp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00161a015
更新日期：1986-11-01 00:00:00
abstract：:Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701478a
更新日期：2008-06-26 00:00:00
abstract：:A series of base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine, a carbocyclic nucleoside, were synthesized and evaluated as inhibitors of S-adenosyl-L-methionine-dependent methyltransferases, including catechol O-methyltransferase, phenylethanolamine N-methyltransferase, and histamine N-methyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00382a016
更新日期：1985-04-01 00:00:00
abstract：:A series of pyridine-2-carboxaldehyde N-oxide and pyridine-2-carboxaldehyde (thio)phosphoric hydrazones and two cupric chelates was synthesized. The hydrazones, chelates, and combinations of hydrazones and cupric chloride were tested against mice bearing P388 lymphocytic leukemia, Sarcoma 180, or Ehrlich carcinoma asc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00209a011
更新日期：1978-11-01 00:00:00
abstract：:N,N'-Diarylureas were prepared, and the structure-activity relationship relative to the CXCR2 receptor was examined. This led to the identification of a potent and highly selective CXCR2 antagonist, which in addition was shown to be functionally active both in vitro against human neutrophils and in vivo in rabbit mode...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm034248l
更新日期：2004-03-11 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：:The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of poten...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01203
更新日期：2020-10-08 00:00:00
abstract：:Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. O...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0105777
更新日期：2002-05-23 00:00:00
abstract：:A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progresse...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01793
更新日期：2021-01-14 00:00:00
abstract：:Collective experience in structure-based lead progression has found electrostatic interactions to be more difficult to optimize than shape-based ones. A major reason for this is that the net electrostatic contribution observed includes a significant nonintuitive desolvation component in addition to the more intuitive ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm051105l
更新日期：2006-04-20 00:00:00
abstract：:Compound 2 [4-amino-N-(2,6-dimethylphenyl)benzamide] is an effective anticonvulsant in several animal models. For example, following oral administration to mice, it antagonized maximal electroshock (MES) induced seizures with an ED50 of 1.7 mg/kg. During drug disposition studies with 2, we found that it was rapidly me...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00393a010
更新日期：1987-10-01 00:00:00
abstract：:Among the nonclassical cannabinoids, CP-55,244 (4), which incorporates an axial 14 beta-hydroxymethyl group, is pharmacologically 30 times more potent than its prototype CP-47,497 (2) and 300 times more potent than delta 9-THC (1). It has a high degree of stereoselectivity (about 120:1) with respect to its diastereois...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960410r
更新日期：1998-01-15 00:00:00
abstract：:(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300396n
更新日期：2012-05-24 00:00:00
abstract：:HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to comb...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9016027
更新日期：2010-04-22 00:00:00
abstract：:Intrigued by the role of protein acetylation in hepatitis C virus (HCV) replication, we tested known histone deacetylase (HDAC) inhibitors and a focused library of structurally simple hydroxamic acids for inhibition of a HCV subgenomic replicon. While known HDAC inhibitors with varied inhibitory profiles proved to be ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501330g
更新日期：2015-01-22 00:00:00
abstract：:A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00397
更新日期：2016-07-28 00:00:00
abstract：:A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biologic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980366a
更新日期：1998-10-22 00:00:00
abstract：:Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9706933
更新日期：1998-03-26 00:00:00
abstract：:The ability to develop a chemical into a drug depends on multiple factors. Beyond potency and selectivity, ADME/PK and the toxicological profile of the compound play a significant role in its evaluation as a candidate for development. Those factors are being brought into bear earlier in the discovery process and even ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0004594
更新日期：2001-08-16 00:00:00
abstract：:A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive bindin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049554t
更新日期：2004-11-04 00:00:00
abstract：:It is now accepted that (-)-cocaine binds to specific recognition sites associated with monoamine transporters in the mammalian brain. In this study, several analogs of 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester were prepared and their potency for inhibiting the binding of [3H]-3 beta-(4-fluorophenyl)tro...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00059a010
更新日期：1993-04-02 00:00:00
abstract：:The leukotrienes, metabolites of arachidonic acid produced through the action of the enzyme 5-lipoxygenase, are important mediators of immediate hypersensitivity and inflammation. Among the variety of diseases in which the leukotrienes may play a symptomatic or causative role is the dermatological condition psoriasis,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00165a005
更新日期：1990-03-01 00:00:00
abstract：:3',5'-Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger that regulates numerous biological processes under physiological and pathological conditions, including cancer, diabetes, heart failure, inflammation, and neurological disorders. In the past, all effects of cAMP were initially believed to be med...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm401425e
更新日期：2014-05-08 00:00:00
abstract：:The synthesis of the benzothiopyranoindazoles, a new class of chromophore modified anthracenediones related to mitoxantrone, is described. In this structural class the quinone moiety, which is believed to be responsible for the cardiotoxicity of the anthracyclines, has been designed out. The synthesis of the benzothio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00403a009
更新日期：1988-08-01 00:00:00
