Abstract:
:Glycogen synthase kinase 3beta (GSK-3beta) inhibition is expected to be a promising therapeutic approach for treating Alzheimer's disease. Previously we reported a series of 1,3,4-oxadiazole derivatives as potent and highly selective GSK-3beta inhibitors, however, the representative compounds 1a,b showed poor pharmacokinetic profiles. Efforts were made to address this issue by reducing molecular weight and lipophilicity, leading to the identification of oxadiazole derivatives containing a sulfinyl group, (S)-9b and (S)-9c. These compounds exhibited not only highly selective and potent inhibitory activity against GSK-3beta but also showed good pharmacokinetic profiles including favorable BBB penetration. In addition, (S)-9b and (S)-9c given orally to mice significantly inhibited cold water stress-induced tau hyperphosphorylation in mouse brain.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Saitoh M,Kunitomo J,Kimura E,Iwashita H,Uno Y,Onishi T,Uchiyama N,Kawamoto T,Tanaka T,Mol CD,Dougan DR,Textor GP,Snell GP,Takizawa M,Itoh F,Kori Mdoi
10.1021/jm900647esubject
Has Abstractpub_date
2009-10-22 00:00:00pages
6270-86issue
20eissn
0022-2623issn
1520-4804journal_volume
52pub_type
杂志文章abstract::The synthesis and in vitro antiplatelet activity significant data of coumarin derivatives 5i-x and quinolin-2(1H)-one derivatives 22a,b, as well as the corresponding structure-activity relationships are described. The recently reported 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin 5f and its potent 7-(2-morp...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0611511
更新日期:2007-06-14 00:00:00
abstract::To study the influence of substitution of CN for C identical to CH in the anti-herpes virus nucleoside 5-(propynyloxy)-2'-deoxyuridine (1), 5-[(cyanomethylene)oxy]-2'-deoxyuridine (2) was prepared. When the potassium salt of 5-hydroxy-2'-deoxyuridine was reacted with iodoacetonitrile in dry DMF, the bisalkylated produ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00136a007
更新日期:1981-04-01 00:00:00
abstract::A practical combination of comparative modeling and NMR spectroscopy was used to generate a three-dimensional structure of the response regulator protein, Spo0F. The backbone structure obtained compares to the Spo0F Y13S mutant X-ray structure with an rmsd of 2.0 A. We provide results which suggest that structures obt...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970156i
更新日期:1997-10-10 00:00:00
abstract::Various 2',3'-dideoxy-L-cytidine,2',3'-dideoxy-L-uridine, and 3'-deoxy-L-thymidine analogues have been synthesized and evaluated in vitro as potential anti-HIV and anti-HBV agents. Coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (1) with silylated derivatives of 5-fluorocytosine, cytosi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00032a013
更新日期:1994-03-18 00:00:00
abstract::Four new 2-(2-piperidinoethyl)benzocycloalkanone derivatives, 20-23, were prepared and evaluated as potential antipsychotic agents in receptor binding assays for dopamine (DA) and 5-HT2A receptors and in functional and behavioral screens. Their affinities for D2 receptors (Ki's in the nanomolar range: 46.7-70.7) and D...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00042a009
更新日期:1994-08-05 00:00:00
abstract::Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal ce...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm4012438
更新日期:2013-11-27 00:00:00
abstract::The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9910369
更新日期:1999-08-12 00:00:00
abstract::The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00040a004
更新日期:1994-07-08 00:00:00
abstract::A series of N(6)-alkyl-2-alkynyl derivatives of adenosine (Ado) have been synthesized and evaluated for their affinity at human A(1), A(2A), and A(3) receptors and for their potency at A(2B) adenosine receptor subtypes. The corresponding 2-(1-alkynyl) derivatives of 5'-N-ethylcarboxamidoadenosine (NECA) and Ado are us...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0109762
更新日期:2002-07-18 00:00:00
abstract::Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980570y
更新日期:1999-04-08 00:00:00
abstract::The spread of antibiotic-resistant pathogens is a growing concern, and new families of antibacterials are desperately needed. Odilorhabdins are a new class of antibacterial compounds that bind to the bacterial ribosome and kill bacteria through inhibition of the translation. NOSO-95C, one of the first member of this f...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00790
更新日期:2018-09-13 00:00:00
abstract::A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited H...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5001503
更新日期:2014-04-24 00:00:00
abstract::Glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) are proglucagon derived peptides that are released from gut endocrine cells in response to nutrient intake. These molecules are rapidly inactivated by the action of dipeptidyl peptidase IV (DPP-4) which limits their use as therapeutic agents. The rece...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.9b00835
更新日期:2020-02-13 00:00:00
abstract::Fifteen quinolizidine derivatives have been tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. All compounds exhibited from moderate to high antiarrhythmic activity, and five of them (3, 4, 6, 13, and 15) were more active ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100298d
更新日期:2010-06-24 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::A series of alpha,alpha-diaryl-1-piperidinebutanols was evaluated for antiarrhythmic activity in the coronary ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group yielded compounds with the best antiarrhythmic profiles in this series. The length of the methylene ch...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00105a003
更新日期:1991-01-01 00:00:00
abstract::9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione (1) was designed and synthesized as a nonionic inhibitor for the donor binding site of human blood group B galactosyltransferase (GTB). Enzymatic characterization showed 1 to be extremely specific, as the highly homologous human N-acetylgalact...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300642a
更新日期:2013-03-14 00:00:00
abstract::Syntheses of several new analogues of lyngbyatoxin A from a single common intermediate are described. These compounds bear a carbon chain at the 7-position of the indolactam V (ILV) nucleus which contains either a hydrophilic or a lipophilic group. The effect of these minor structural alterations on the ability of the...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00112a017
更新日期:1991-08-01 00:00:00
abstract::A series of 3-indoleacrylonitrile tyrphostins, 2-chloro-3-phenylquinolines, and 3-arylquinoxalines were prepared and tested for inhibition of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The potency of the inhibitors was found to be quinoxalines > quinolines > indoles. Lipophilic groups...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950727b
更新日期:1996-05-24 00:00:00
abstract::The construction of bioactive peptides using β-amino acid-containing sequence patterns is a very promising strategy to obtain analogues that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5010896
更新日期:2014-12-11 00:00:00
abstract::2,9beta-Dimethyl-2'-hydroxy-6,7-benzomorphan (18) has been synthesized from m-methoxyphenylacetone (6a) or m-methoxyphenylacetonitrile (1) via bromo-alpha-tetralone (10). Isomeric bromo-alpha-tetralone 9, instead of undergoing cyclization to a 6,7-benzomorphan, gave aromatization product 12. The structures and stereoc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00242a005
更新日期:1975-08-01 00:00:00
abstract::A number of 7-amino and 7-acylamino substituted 4,4a-dihydro-5H-indeno[1,2-c]pyridazin-3-ones have been synthesized as rigid congeners of hypotensive 6-aryl-5-methyl-4,5-dihydro-3(2H)-pyridazinones and tested as antihypertensive, antithrombotic, antiulcer, and antiinflammatory agents. Unlike the previously described 7...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00161a010
更新日期:1986-11-01 00:00:00
abstract::New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are ca...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400529f
更新日期:2013-06-13 00:00:00
abstract::Three types of brassinosteroid analogues with perfluoroalkylated side chains were synthesized by using alkene cross-metathesis of a brassinosteroid derivative bearing a terminal alkene moiety with different (perfluoroalkyl)propenes. The presence of the double bonds in the cross-metathesis products allowed a facile one...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900495f
更新日期:2009-09-24 00:00:00
abstract::We have previously described the potent and selective inhibition of several strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11-tetraazamacrocyclic (cyclam) ring system. Upon further investigation, we have also found that incorporating an aromat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00002a019
更新日期:1995-01-20 00:00:00
abstract::From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030951y
更新日期:2004-02-12 00:00:00
abstract::Uridine (Urd) is a promising biochemical modulator to reduce host toxicity caused by 5-fluorouracil (5-FU) without impairing its antitumor activity. Elevated doses of Urd are required to achieve a protective effect against 5-FU toxicity, but exogenous administration of Urd is not well-tolerated. Selective inhibitors o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401389u
更新日期:2013-11-14 00:00:00
abstract::Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systema...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0490540
更新日期:2005-07-14 00:00:00
abstract::Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-penta...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00995
更新日期:2019-10-10 00:00:00
abstract::Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and d...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.8b00370
更新日期:2018-09-27 00:00:00