Abstract：
:From salicyclic acid, the two enantiomers of N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14% radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide-125 and chloramine-T gave [125I](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of [125I](S)-6b and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenates using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD = 1.2 nM) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [125I](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1, 60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 receptors indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
de Paulis T,Janowsky A,Kessler RM,Clanton JA,Smith HEdoi
10.1021/jm00118a031subject
Has Abstractpub_date
1988-10-01 00:00:00pages
2027-33issue
10eissn
0022-2623issn
1520-4804journal_volume
31pub_type
杂志文章abstract：:We recently described the discovery of a dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1). Here we report a structure-guided design in combination with structure-activity relationship studies to exploit the difference in the p2 binding pocket of Bcl-2 and Mcl-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101181u
更新日期：2011-02-24 00:00:00
abstract：:A series of N-aryl-N'-(2-chloroethyl)ureas (CEUs) and derivatives were synthesized and evaluated for antiproliferative activity against a wide panel of tumor cell lines. Systematic structure--activity relationship (SAR) studies indicated that: (i) a branched alkyl chain or a halogen at the 4-position of the phenyl rin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0010264
更新日期：2001-03-01 00:00:00
abstract：:In the past few years the focus on central acetylcholine receptors has shifted from compounds with affinity for muscarinic acetylcholine receptors (mAChR) to compounds with affinity for nicotinic acetylcholine receptors (nAChR). The therapeutic potential includes treatment of a variety of diseases, e.g., Alzheimer's d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990973d
更新日期：2000-06-01 00:00:00
abstract：:Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an "open" conformation or a "closed" conformation. In...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2003766
更新日期：2011-10-13 00:00:00
abstract：:To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essent...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060736s
更新日期：2006-11-02 00:00:00
abstract：:A series of N7-substituted 7-aminoactinomycin D analogues with alkyl, aralkyl, and heteroaralkyl substituents was synthesized and their biological properties were studied. All of these analogues proved to be 22- to 28-fold less toxic than actinomycin D when tested against human lymphoblastic leukemia cells (CCRF-CEM) ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00207a021
更新日期：1978-09-01 00:00:00
abstract：:A series of amide analogues of the 2,2'-dithiobis(1H-indole-3-alkaonic acid) class of tyrosine kinase inhibitors have been prepared, by reaction of 1H-indole-3-alkanamides (8) with S2Cl2, and separation of the desired disulfides from the initial mixtures of mono-, di-, and trisulfides formed. These amides were evaluat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00031a009
更新日期：1994-03-04 00:00:00
abstract：:The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the va...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.6b01575
更新日期：2017-07-13 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：:Family 18 chitinases play an essential role in a range of pathogens and pests. Several inhibitors are known, including the potent inhibitors argadin and allosamidin, and the structures of these in complex with chitinases have been elucidated. Recent structural analysis has revealed that CI-4 [cyclo-(L-Arg-D-Pro)] inhi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049940a
更新日期：2004-11-04 00:00:00
abstract：:It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00107
更新日期：2018-04-26 00:00:00
abstract：:We have synthesized a library of thiosemicarbazones and screened them against three parasitic cysteine proteases, cruzain, falcipain-2, and rhodesain, and against the respective parasite sources of these three proteases, Trypanosoma cruzi, Plasmodium falciparum, and Trypanosoma brucei. The screens identified compounds...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030549j
更新日期：2004-06-03 00:00:00
abstract：:A series of new amine cyanoborane derivatives were synthesized and exhibited antifungal activity. A long alkyl chain attached to the nitrogen of the amine cyanoboranes and carboxyboranes enhances antifungal activity. An enhanced activity was also obtained upon the halogenation of the amine cyanoboranes as well as in t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060476e
更新日期：2006-08-10 00:00:00
abstract：:The synthesis and antiviral activity of a number of 3'-C-difluoromethyl and 3'-deoxy-3'-C-fluoromethyl nucleosides are reported. The 3'-C-difluoromethyl nucleosides 26a and 26b were obtained by treatment of the corresponding 2',5'-di-O-protected-3'-C-formyl nucleosides 25a and 25b with (diethylamino)sulfur trifluoride...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00171a024
更新日期：1990-09-01 00:00:00
abstract：:Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine gre...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01682
更新日期：2019-02-28 00:00:00
abstract：:The discovery and structure-activity relationship of first-generation small-molecule malonyl-CoA decarboxylase (MCD; CoA = coenzyme A) inhibitors are reported. We demonstrated that MCD inhibitors increased malonyl-CoA concentration in the isolated working rat hearts. Malonyl-CoA is a potent, endogenous, and allosteric...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050109n
更新日期：2006-03-09 00:00:00
abstract：:We previously reported (J. Med. Chem. 1993, 36, 1188-1193) that changes to the ring size of the piperidine and cyclohexyl rings of the high-affinity and selective dopamine (DA)-uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 2) caused different, and in some cases opposite, changes in affinity for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00077a011
更新日期：1993-12-10 00:00:00
abstract：:9-acridinyl derivatives of 1,6-hexanediamine, 1,8-octanediamine, bis(3-aminopropyl)amine, N,N'-bis(3-amino-propyl)piperazine, and N-ethyl-1,6-hexanediamine in the form of their hydrochlorides were prepared in high yields and converted into potential hetero bis DNA intercalating diacridines. The corresponding potential...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00364a028
更新日期：1983-10-01 00:00:00
abstract：:The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00606
更新日期：2017-09-14 00:00:00
abstract：:A series of 1-aminopropan-2-ols were synthesized and evaluated against two strains of malaria, Plasmodium falciparum FCR3 (chloroquine-resistant) and 3D7 (chloroquine-sensitive). Microwave-assisted ring opening of epoxides (aryl and alkyl glycidyl ethers, glycidol, epichlorohydrin) with various amines without catalyst...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070553l
更新日期：2007-08-23 00:00:00
abstract：:An endogenous heptadecapeptide, nociceptin/orphanin FQ (N/OFQ), and a G-protein-coupled receptor, N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor], have been described in terms of its structure, distribution, and pharmacology. Thus, the N/OFQ and NOP receptor are located in the central nervous ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm7012979
更新日期：2009-02-12 00:00:00
abstract：:To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been de...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020839k
更新日期：2002-09-12 00:00:00
abstract：:The DEDDh family of exonucleases plays essential roles in DNA and RNA metabolism in all kingdoms of life. Several viral and human DEDDh exonucleases can serve as antiviral drug targets due to their critical roles in virus replication. Here using RNase T and CRN-4 as the model systems, we identify potential inhibitors ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00794
更新日期：2016-09-08 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：:Fourteen structurally diverse Annonaceous acetogenins, representing the three main classes of bis-adjacent, bis-nonadjacent, and single-THF ring(s), were tested for their ability to inhibit the growth of adriamycin resistant human mammary adenocarcinoma (MCF-7/Adr) cells. This cell line is resistant to treatment with ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9700169
更新日期：1997-06-20 00:00:00
abstract：:Epigenetic regulators that exhibit aberrant enzymatic activities or expression profiles are potential therapeutic targets for cancers. Specifically, enzymes responsible for methylation at histone-3 lysine-9 (like G9a) and aberrant DNA hypermethylation (DNMTs) have been implicated in a number of cancers. Recently, mole...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01925
更新日期：2018-08-09 00:00:00
abstract：:The steroidal sulfonylpyrazole 1 bound to the rat ventral prostate androgen receptor in vitro; it inhibited testosterone propionate induced increases in ventral prostate weight in vivo in the castrated, immature male rat with an ED50 of 15 mg/kg po. Compound 1 lacked androgenic activity in vivo in contrast to the pare...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00170a008
更新日期：1990-08-01 00:00:00
abstract：:Novel analogues of the class III antiarrhythmic agent 1-[2-hydroxy-2-[4-[(methylsulfonyl)amino]phenyl]ethyl]-3-methyl-1H- imidazolium chloride, 1 (CK-1649), were prepared and investigated for their class III electrophysiological activity on isolated canine cardiac Purkinje fibers and ventricular muscle tissue. Structu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00395a021
更新日期：1987-12-01 00:00:00
abstract：:PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in wate...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050700k
更新日期：2006-02-09 00:00:00
abstract：:The (E)- and (Z)-m-(trifluoromethyl)-alpha, beta-dimethylcinnamamides and some of their N-alkyl derivatives were prepared and pharmacologically tested as anticonvulsant agents in order to verify if a ring substituent, like the m-CF3 group, different from a halogen but possessing the same electronic effect could lead t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00137a010
更新日期：1981-05-01 00:00:00
