Abstract:
:The photolabile (diazomethyl)carbonyl function was introduced into the 8-position of 2-(N,N-di-n-propyl-amino)-1,2,3,4-tetrahydronaphthalene in three ways, resulting in the ether 8-[[(diazomethyl)carbonyl]methoxy]-2-(N,N-di-n-propylamino)-1,2,3,4- tetrahydronaphthalene (2), the ester 8-(diazoacetoxy)-2-(N,N-di-n-propyl-amino)-1,2,3,4- tetrahydronaphthalene (3), and the ketone 8-[(diazomethyl)carbonyl]-2-(N,N-di-n-propylamino)- 1,2,3,4-tetrahydronaphthalene (4). Specific binding of these compounds at the 5-hydroxytryptamine1A sites in rat brain membranes labeled with 1 nM [3H]-8-hydroxy-2-(N,N-di-n-propylamino)- 1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) showed IC50 values of ca. 75, 125, and 25 nM, respectively, for the three compounds. Photolysis of methanolic solutions of 2-4 in the absence of receptor proteins lead in each case to an abundance of Wolff-rearranged products. In the case of ether 2, subsequent beta-elimination to 8-OH-DPAT removed this compound from serious consideration as a photoaffinity ligand. Ester 3 and ketone 4 were photolysed in vitro. Whereas ester 3 was ineffective in decreasing the specific binding of [3H]-8-OH-DPAT, ketone 4 decreased 40% of the specific binding of [3H]-8-OH-DPAT in the presence (but not the absence) of ultraviolet light. Thus this ketone emerges from these studies as a good candidate for a photoaffinity label for the 5-hydroxytrypatamine1A receptor.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kline TB,Nelson DL,Namboodiri Kdoi
10.1021/jm00165a011subject
Has Abstractpub_date
1990-03-01 00:00:00pages
950-5issue
3eissn
0022-2623issn
1520-4804journal_volume
33pub_type
杂志文章abstract::Four steroidal nitrosoureas with structures which may permit specific binding to estrogen receptor were synthesized. Inhibitory activity was observed against the growth of the DMBA-induced transplantable rat mammary tumor 13762. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00188a015
更新日期:1979-02-01 00:00:00
abstract::A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration proces...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8003784
更新日期:2008-08-28 00:00:00
abstract::A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01329
更新日期:2020-11-25 00:00:00
abstract::A novel series of substituted (pyrroloamino)pyridines was synthesized, and the compounds were evaluated for cholinomimetic-like properties in vitro (inhibition of [3H]quinuclidinyl benzilate binding) and in vivo (reversal of scopolamine-induced dementia) as potential agents for the treatment of Alzheimer's disease. Co...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950644v
更新日期:1996-01-19 00:00:00
abstract::The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing saturated bicyclic amino acids in place of proline is described. Octahydroindole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, and octahydro-3-oxoisoindole-1-carboxylic acid can replace proline in both sulfh...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00389a006
更新日期:1987-06-01 00:00:00
abstract::(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm034073f
更新日期:2003-07-17 00:00:00
abstract::Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of E...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00421
更新日期:2018-06-14 00:00:00
abstract::A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar b...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010417v
更新日期:2002-02-14 00:00:00
abstract::In previous reports illustrating the effects of conformational restriction of the N-terminal region of human pancreatic growth hormone releasing factor, we demonstrated that D-amino acid substitutions in either of positions 1, 2, or 3 resulted in greatly increased growth hormone releasing activity both in vivo and in ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00380a006
更新日期:1985-02-01 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::Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, c...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501345y
更新日期:2015-01-22 00:00:00
abstract::The synthesis of a novel series of antitussive agents is described. Two series of amino-substituted tetra- and hexahydrodibenzofurans were prepared and examined for antitussive activity in the guinea pig after cough elicited by electrical stimulation of the vagus nerve. A significant level of activity, comparable with...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00212a003
更新日期:1977-02-01 00:00:00
abstract::Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) has been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401884z
更新日期:2014-03-27 00:00:00
abstract::A series of tetramisole derivatives was synthesized and tested for inhibitory activity against alkaline phosphatase which was partially purified from a murine ascitic neoplasm resistant to 6-thiopurines (Sarcoma 180/TG). These agents included derivatives substituted with halogens, CH3, or NO2 groups at either the meta...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00214a021
更新日期:1977-04-01 00:00:00
abstract::The 5'-phosphate (1) of the antiviral nucleoside 5-cyano-2'-deoxyuridine was synthesized and evaluated for inhibition of thymidylate synthetase purified from methotrexate-resistant Lactobacillus casei. Compound 1 was a potent competitive inhibitor with a K1 of 0.55 microns. Irreversible enzyme inhibition by this compo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00195a028
更新日期:1979-09-01 00:00:00
abstract::A variation of the bromine substitution from 6- to 7-position converts the glycogen synthase kinase-3alpha/beta-(GSK-3-alpha/beta) selective inhibitor 6-bromoindirubin-3'-oxime (6BIO) to a potent inhibitor of Aurora B and C kinases. The novel indirubin analogue 7-bromoindirubin-3'-oxime (7BIO) demonstrated unexpected ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm070077z
更新日期:2007-08-23 00:00:00
abstract::In a study of nonsteroidal antiinflammatory and analgesic agents, a series of 1,3-dihydro-3-(substituted phenyl)imidazo[4,5-b]pyridin-2-ones-and 3-(substituted phenyl)triazolo[4,5-b]pyridines was prepared. Many of the imidazolones were alkylated on the free nitrogen. In a modified Randall-Selitto analgesic assay, the ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00207a023
更新日期:1978-09-01 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::Doxazolidine (doxaz) is a new anthracycline anticancer agent. While structurally similar to doxorubicin (dox), doxaz acts via a distinct mechanism to selectively enhance anticancer activity over cardiotoxicity, the most significant clinical impediment to successful anthracycline treatment. Here, we describe the synthe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300714p
更新日期:2012-07-26 00:00:00
abstract::Several 4-benzyl analogues of 5-ethyl-6-methyl-4-(phenylthio)pyridin-2(1H)-ones were synthesized and evaluated for their anti-HIV-l activities. Key transformations include metalation at the 4-C-position of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5) and its coupling with benzyl bromide or benzaldehyde deriv...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0009437
更新日期:2000-10-19 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::The receptor CRM1 is responsible for the nuclear export of many tumor-suppressor proteins and viral ribonucleoproteins. This renders CRM1 an interesting target for therapeutic intervention in diverse cancer types and viral diseases. Structural studies of Saccharomyces cerevisiae CRM1 ( Sc ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c00143
更新日期:2020-07-23 00:00:00
abstract::A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00254
更新日期:2017-05-11 00:00:00
abstract::Novel 5-[(alkylamino)methyl]thieno[2,3-b]furan-2-sulfonamides were prepared and evaluated in vitro for inhibition of human carbonic anhydrase II (CA II) and ex vivo for their ability to inhibit Ca II in the albino rabbit eye after topical administration. Compound 11a was found to lower intraocular pressure (IOP) in bo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00094a016
更新日期:1992-08-07 00:00:00
abstract::The sulfoxides 5-methylsulfinyl-2-furaldehyde semicarbazone (2) and 1-[(5-methylsulfinyl-2-fufurylidene)amino]hydantoin (3) as well as the sulfones 1-[(5-methylsulfonyl-2-furfurylidene)animo]hydantoin (1) and 1-(5-methylsulfonly-2-furyl)-2-(6-amino-3-p-ridazyl)ethylene hydrochloride (4) have been prepared and tested f...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00245a030
更新日期:1975-11-01 00:00:00
abstract::In search of water-soluble artemisinin derivatives that are more stable than sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5) were synthesized and tested in mice. All products tested (except 5a and 5b) are the beta isomers. These basic compounds combined with organic acids (oxalic acid,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm990552w
更新日期:2000-04-20 00:00:00
abstract::Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorubicin (12, 14) were designed and synthesized. They are self-immolative prodrugs for suicide gene therapy activation by the enzyme carboxypeptidase G2 (CPG2) subsequently releasing the corresponding anthracyclines, by a 1,6-elimination mechanism....
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980696v
更新日期:1999-07-01 00:00:00
abstract::(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple f...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00121a034
更新日期:1989-01-01 00:00:00
abstract::Recent studies have indicated several therapeutic applications for delta opioid agonists and antagonists. To exploit the therapeutic potential of delta opioids developing a structural basis for the activity of ligands at the delta opioid receptor is essential. The conformationally sampled pharmacophore (CSP) method (B...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0612463
更新日期:2007-04-19 00:00:00
abstract::The aim of this work was to obtain photoactivatable nonpeptide antagonists of the angiotensin II AT(1) receptor. Based on structure-function relationships, two chemical structures as well as appropriate synthetic schemes were chosen as a frame for the design of radiolabeled azido probes. The feasibility of the strateg...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm991050l
更新日期:1999-11-04 00:00:00