Abstract:
:A new and extensive set of 4-(6-iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine (IMPY) derivatives was synthesized and assayed for affinity toward human Abeta plaques. 6-Ethylthio- (12h), 6-cyano- (12e), 6-nitro- (12f), and 6-p-methoxybenzylthio- (15d) analogues were discovered to have high affinity (KI < 10 nM). However, introduction of a hydrophilic thioether group in the 6-position (15a-c, 15e-g) reduced or abolished affinity. In secondary N-methyl analogues, a bromo substituent in the adjacent ring position (14a) imparted high affinity (KI = 7.4 nM) whereas a methyl substituent did not (14c). The tolerance for nonhydrophilic thioether substituents in the 6-position opens up the possibility of developing new sensitive positron emission tomography radioligands for imaging human Abeta plaques in Alzheimer's disease, especially in view of the amenability of thioethers to be labeled with carbon-11 or fluorine-18 through S-alkylation reactions. The structure-activity relationships revealed in this study extends insight into the topography of the binding site for IMPY-like ligands in human Abeta plaques.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Cai L,Cuevas J,Temme S,Herman MM,Dagostin C,Widdowson DA,Innis RB,Pike VWdoi
10.1021/jm0702231subject
Has Abstractpub_date
2007-09-20 00:00:00pages
4746-58issue
19eissn
0022-2623issn
1520-4804journal_volume
50pub_type
杂志文章abstract::A 256-compound library was evaluated in an anti-HIV screen to identify structural "mimics" of the fused tetracyclic indole compound 1 (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01357
更新日期:2016-03-10 00:00:00
abstract::The enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) catalyzes the final step in the biosynthesis of epinephrine and is a potential drug target, primarily for the control of hypertension. Unfortunately, many potent PNMT inhibitors also possess significant affinity for the a2-adrenoceptor, which compli...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01475
更新日期:2020-11-25 00:00:00
abstract::Hydroxylated, methoxylated, and/or chlorinated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines were generally synthesized out of substituted 2-phenylethylamines and isochromanones by Bischler-Napieralski cyclization of the resulting benzamides to dibenzoquinolizines and the quaternization and cleavage of the centra...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm051237e
更新日期:2006-03-23 00:00:00
abstract::Several 1,3-disubstituted and 1-substituted derivatives of 5-propionoxy-5-(1-phenylethyl)barbituric acid were synthesized and evaluated for analgesic activity. Three of these compounds, 1,3-bis(methoxymethyl)-5-propionoxy-5-(1-phenylethyl)barbituric acid (2), 1,3-dimethyl-5-propionoxy-5-(1-phenylethyl)barbituric acid...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00241a010
更新日期:1975-07-01 00:00:00
abstract::Oxadiazoles, like the benzoyl group in a series of imidazo[1,2-a]pyrimidines, have been found to be metabolically stable alternatives to ester groups in benzodiazepine-receptor ligands. This change has lead to a number of compounds which bind to the receptors and which exhibit potent agonist activity in a food-motivat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00111a021
更新日期:1991-07-01 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::A series of 9-(hydroxyalkenyl)purines (adenines and 3-deazaadenines), which are analogues of neplanocin A, were synthesized. The analogues were tested as inhibitors of bovine liver and murine L929 cell S-adenosyhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as inhibitors of vaccinia virus replication in murine L929 ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00117a011
更新日期:1988-09-01 00:00:00
abstract::A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-positi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0611509
更新日期:2007-03-08 00:00:00
abstract::A new class of acyclic adenosine analogues is described which exhibit broad-spectrum antiviral activity and are apparently targeted at S-adenosyl-L-homocysteine hydrolase. The compounds are all alkyl (i.e., methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl, tert-butyl, 1-pentyl, 3-methylbutyl, 1-octy...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00381a004
更新日期:1985-03-01 00:00:00
abstract::A novel cytochrome P450, CYP53A15, was identified in the pathogenic filamentous ascomycete Cochliobolus lunatus. The protein, classified into the CYP53 family, was capable of para hydroxylation of benzoate. Benzoate is a key intermediate in the metabolism of aromatic compounds in fungi and yet basically toxic to the o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800030e
更新日期:2008-06-26 00:00:00
abstract::Syntheses of several tripeptide analogues of leupeptin containing C-terminal argininal, lysinal, or ornithinal units are presented. The synthetic analogues were tested as inhibitors of trypsin, plasmin, and kallikrein. (Benzyloxycarbonyl)-L-leucyl-L-leucyl-L-argininal (2a) was significantly less effective as an inhibi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00163a014
更新日期:1990-01-01 00:00:00
abstract::In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bou...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm4001242
更新日期:2013-07-11 00:00:00
abstract::Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1-3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several ty...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500034j
更新日期:2014-06-12 00:00:00
abstract::A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial act...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00106a029
更新日期:1991-02-01 00:00:00
abstract::Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0707166
更新日期:2007-11-15 00:00:00
abstract::A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and evaluated by the radioligand binding assay and the anticonvulsant effects in the mouse NMDA-induced seizure model. Among them, derivatives of 3S-(-)-4 such as 3a, 3f, and 3g which had certain zwitterionic anilides showed high affinity to t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020239l
更新日期:2003-02-27 00:00:00
abstract::The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its me...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701093y
更新日期:2008-02-28 00:00:00
abstract::Modulation of sphingosine 1-phosphate (S1P) signaling represents a solid opportunity for multiple sclerosis (MS) treatment. In this issue, a team at Novartis reports on the identification of the first direct S1P lyase (S1PL) inhibitors as new MS agents. One of the most potent inhibitors reported in their work was demo...
journal_title:Journal of medicinal chemistry
pub_type: 评论,杂志文章
doi:10.1021/jm500845y
更新日期:2014-06-26 00:00:00
abstract::A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the mos...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00237a016
更新日期:1975-03-01 00:00:00
abstract::Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed, synthesized, and evaluated as antitumor agents. Compounds ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm058234m
更新日期:2005-11-17 00:00:00
abstract::Androgens are well-known to stimulate prostate cancer (PC) growth. Thus, blockade of androgen production in testes and adrenals by CYP17 inhibition is a promising strategy for the treatment of PC. Moreover, many PC patients suffer from glucocorticoid overproduction, and importantly mutated androgen receptors can be st...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100317b
更新日期:2010-08-12 00:00:00
abstract::Analogues of the antimycotic allylamine terbinafine were prepared in which the naphthalene and the tert-butyl-acetylene moieties were preserved, but the spacer between these two groups was varied, and the antifungal activity of the new compounds was evaluated. All modifications of the original spacer such as reduction...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00031a010
更新日期:1994-03-04 00:00:00
abstract::125I-labeled (E)-18-iodo-17-octadecenoic acid (13) has been prepared and evaluated in rats to determine the myocardial uptake and retention and degree of in vivo deiodination of this model iodovinyl-substituted fatty acid, which contains no structural perturbation to inhibit metabolism. This new agent was prepared by ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00367a021
更新日期:1984-01-01 00:00:00
abstract::In an effort to determine the stereochemical requirements for pharmacological activity among the series of nonclassical cannabinoids synthesized at Pfizer, we have studied the conformational properties of the parent bicyclic analog CP-47,497. For this study, we have used a combination of solution NMR and theoretical c...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00036a006
更新日期:1994-05-13 00:00:00
abstract::(R,S)-2-Amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid ((R,S)-APPA) is the only partial agonist at the (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors so far described. In light of the pharmacological interest in partial agonists, we have now a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00033a003
更新日期:1994-04-01 00:00:00
abstract::Class A-class C mechanism-based beta-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin again...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm034056q
更新日期:2003-06-19 00:00:00
abstract::The cytotoxic activities of new 2-alkyl-4,6-dihetero(N,O)alkyl-1,3,5-triazines toward selected tumor cell lines have been evaluated, and for the first time, the potential of 2-alkyl-4,6-dialkoxy-1,3,5-triazines has been shown. ...
journal_title:Journal of medicinal chemistry
pub_type: 信件
doi:10.1021/jm0495374
更新日期:2004-09-09 00:00:00
abstract::Two routes for the synthesis of 6-substtituted 8-azaguanosine analogues are described. 2,5,6-Triamino-4(3H)-pyrimidinethione (1) was converted by methylation, nitrosation, and acetylation to -n-acetyl-7-(methylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-5-amine (5). The reaction of 5 with 2,3,5-tri-O-acetyl-D-ribofuranosy...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00232a004
更新日期:1976-10-01 00:00:00
abstract::The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline 1, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin1), wh...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm101144f
更新日期:2010-10-14 00:00:00
abstract::We have developed a fast and robust computational method for prediction of antiviral activity in automated de novo design of HIV-1 reverse transcriptase inhibitors. This is a structure-based approach that uses a linear relation between activity and interaction energy with discrete orientation sampling and with localiz...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049534r
更新日期:2005-03-24 00:00:00