Abstract:
:A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kazuta Y,Hirano K,Natsume K,Yamada S,Kimura R,Matsumoto S,Furuichi K,Matsuda A,Shuto Sdoi
10.1021/jm020415qkeywords:
subject
Has Abstractpub_date
2003-05-08 00:00:00pages
1980-8issue
10eissn
0022-2623issn
1520-4804journal_volume
46pub_type
杂志文章abstract::Serotonin N-acetyltransferase, also called the melatonin rhythm enzyme, is thought to play an important regulatory role in circadian rhythm in animals and people. A series of analogues were synthesized in which indole and coenzyme A were linked via ketone tethers as designed inhibitors of this enzyme. These compounds ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010049v
更新日期:2001-07-19 00:00:00
abstract::The compounds N6-allyl-, N6-isopropyl-, N6-propargyl-, and N6-(2-methylallyl)adenosine were prepared by reacting 6-chloropurine riboside with an excess of the corresponding amines in ethanol, in the presence of two acid acceptors resulting in virtually quantitative yields. The compounds showed biological activity in a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00186a031
更新日期:1980-12-01 00:00:00
abstract::Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01704
更新日期:2019-04-11 00:00:00
abstract::The recently discovered nicotinic agonist pyrido[3,4-b]norhomotropane [corrected] (PHT) as well as its N-methyl and 2'-methyl derivatives (syntheses reported herein) were compared with nicotine, nornicotine, and anatoxin a in a series of in vitro and in vivo assays. The results reveal that PHT possesses activity compa...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00398a004
更新日期:1988-03-01 00:00:00
abstract::Hydrogen sulfide (H2S) is now recognized as a physiologically important gasotransmitter. Compounds which release H2S slowly are sought after for their potential in therapy. Herein the synthesis of a series of phosphordithioates based on 1 (GYY4137) are described. Their H2S release profiles are characterized using 2,6-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00848
更新日期:2015-08-27 00:00:00
abstract::Nitrosourea derivatives of ergolines have been synthesized for the purpose of obtaining agents with both prolactin-and tumor-inhibitory activity. Two derivatives of 8-amino-6-methylergoline (3), 8-[3-(2-chloroethyl)-3-nitrosoureido]-1-nitroso-6-methylergoline (5c) and 8-[3-2-chloroethyl)-3-nitrosoureido]-6-methylergol...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00187a008
更新日期:1979-01-01 00:00:00
abstract::The conformation of the sodium salt of mycophenolic acid (MPA), a potent inhibitor of inosine monophosphate dehydrogenase (IMPD), derived from 1D DIFNOE and 2D ROESY experiments in water and molecular dynamics (MD) is described. The hexenoic acid side chain conformation consistent with the NMR data was similar to that...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950600m
更新日期:1996-03-15 00:00:00
abstract::Aiming to image NTS1 overexpressing tumors, the diarylpyrazole glycoconjugate 8, derived from the potent NTS1 antagonist SR142948A, was synthesized taking advantage of the palladium-catalyzed aminocarbonylation reaction. The glycoconjugate 8 displayed excellent affinity and selectivity toward NTS1. Radiosynthesis proc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401491e
更新日期:2013-11-27 00:00:00
abstract::Potential E- and P-selectin inhibitors were synthesized to explore a hydrophobic area on the E-selectin surface and the PSGL-1 protein binding site on the P-selectin surface that was recently defined by crystallography. Three series of mannose-based compounds (libraries A, B, and C) were synthesized using solution pha...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010390f
更新日期:2002-04-11 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::The inhibitory effect of 108 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines on murine L5178Y tumor cells, resistant and sensitive to methotrexate (MTX), has been studied. From the pI50 values, quantitative structure-activity relationships have been formulated which show that the lipophilic tri...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00369a019
更新日期:1984-03-01 00:00:00
abstract::A series of 26 derivatives of the novel muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for muscarinic and antimuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and uri...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950455c
更新日期:1996-08-16 00:00:00
abstract::A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-alpha]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, al...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960070+
更新日期:1996-09-13 00:00:00
abstract::The cyclic somatostatin analogue cyclo[Pro(1)-Phe(2)-D-Trp(3)-Lys(4)-Thr(5)-Phe(6)] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049500j
更新日期:2005-04-21 00:00:00
abstract::The corticotropin release factor 2 receptor (CRF2R) has many biological activities including modulation of the stress response. Recently, we have demonstrated that CRF2R activation functions to prevent skeletal muscle wasting resulting from a variety of physiological stimuli. Thus we are interested in identifying CRF2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049490m
更新日期:2005-01-13 00:00:00
abstract::The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described. Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs. None ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00115a010
更新日期:1991-11-01 00:00:00
abstract::A series of 2-(2-nitrobenzoyl)cyclohexane-1,3-dione analogues (1-9) were designed, synthesized, and evaluated for inhibition of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), a key enzyme involved in the catabolism of tyrosine which catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. The correlations ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010568y
更新日期:2002-05-23 00:00:00
abstract::The binding and solution-phase properties of six inhibitors of FK506 binding protein (FKBP12) were investigated using free energy perturbation techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neurotrophic activity when bound to FKBP12 a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980062o
更新日期:1998-10-08 00:00:00
abstract::A number of 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3d-d]pyrimidine derivatives that are structurally related to toyocamycin and sangivamycin and the seco nucleosides of tubercidin, toyocamycin, and sangivamycin were prepared and tested for their biological activity. Treatment of the sodium salt of 4-amino-6-brom...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00122a019
更新日期:1989-02-01 00:00:00
abstract::Electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS) have been used for the first time to study the interaction of human alpha-thrombin with methyl 3-(2-methyl-1-oxopropoxy)[1]benzothieno[3,2-b]furan-2-carbox ylate (LY806303; 1), a potent and selective inhibitor whose mechanism of ac...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00068a012
更新日期:1993-08-06 00:00:00
abstract::Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaph...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00006a013
更新日期:1995-03-17 00:00:00
abstract::The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401121k
更新日期:2013-09-12 00:00:00
abstract::Influenza virus (IFV) causes periodic global influenza pandemics, resulting in substantial socioeconomic loss and burden on medical facilities. Yearly variation in the effectiveness of vaccines, slow responsiveness to vaccination in cases of pandemic IFV, and emerging resistance to available drugs highlight the need t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.6b01227
更新日期:2017-05-11 00:00:00
abstract::3-Aminopyrrolidines bearing acyl substituents on either nitrogen and N-acylated 1,4-diazabicyclo[3.2.1]octanes are potent microfilaricides in the Litomosoides carinii gerbil test system but have no effect on adult worms. The high activity of the pyrrolidine derivatives establishes that diethylcarbamazine (DEC) like an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00220a021
更新日期:1977-10-01 00:00:00
abstract::Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm301610q
更新日期:2013-04-11 00:00:00
abstract::An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00186a020
更新日期:1980-12-01 00:00:00
abstract::The synthesis and biological evaluation of a novel paclitaxel photoaffinity probe is described. The synthesis involved the preparation of an azide-containing C13 side chain through a Staudinger cycloaddition followed by a lipase-mediated kinetic resolution to obtain the azetidinone in 99% ee. Coupling of the enantiopu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030581d
更新日期:2004-12-16 00:00:00
abstract::A series of 7-(3-amino- or 3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-o xo-3-quinolinecarboxylic acids was synthesized and tested for antibacterial activity. Unique to these quinolones was the presence of a methyl or phenyl group in the pyrrolidine ring. Although the in vitro activity of th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00164a060
更新日期:1990-02-01 00:00:00
abstract::The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]q...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00085a016
更新日期:1992-04-03 00:00:00
abstract::Extension of the structure-activity relationship studies that led to the discovery of the nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, 2. Compound 2 is a potent an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020068k
更新日期:2003-01-30 00:00:00