Abstract：
:The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening of MGL inhibitors was performed by utilizing a comparative model of the human MGL enzyme. All hit molecules were tested for their potential MGL inhibitory activity, but no compounds were found capable of inhibiting MGL-like enzymatic activity in rat cerebellar membranes. However, these compounds were also tested for their potential FAAH inhibitory activity and five compounds (2-6) inhibiting FAAH were found with IC50 values between 4 and 44 microM. In addition, the hit molecules from the virtual screening of CB2 receptor ligands (reported previously in Salo et al. J. Med. Chem. 2005, 48, 7166) were also tested in our FAAH assay, and four active compounds (7-10) were found with IC50 values between 0.52 and 22 microM. Additionally, compound 7 inhibited MGL-like enzymatic activity with an IC50 value of 31 microM.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Saario SM,Poso A,Juvonen RO,Järvinen T,Salo-Ahen OMdoi
10.1021/jm060394qsubject
Has Abstractpub_date
2006-07-27 00:00:00pages
4650-6issue
15eissn
0022-2623issn
1520-4804journal_volume
49pub_type
杂志文章abstract：:Five new P1-(steroid-21-yl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyro phosphates (ara-CDP-steroids), five 1-beta-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P1-(alkyl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyrophosphat e (ara-CDP-alkyl esters) have been prepared and eva...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a004
更新日期：1985-02-01 00:00:00
abstract：:D-Alanine:D-alanine ligase (Ddl) is an essential ATP-dependent bacterial enzyme involved in peptidoglycan biosynthesis. Discovery of Ddl inhibitors not competitive with ATP has proven to be difficult because the Ddl bimolecular d-alanine binding pocket is very restricted, as is accessibility to the active site for lar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3006965
更新日期：2012-08-09 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：:Structure dependent efficacy studies in the field of selective D4 ligands led to the 2-aminomethyl substituted azaindole 2 (FAUC 213) that displayed strong D4 binding, high subtype selectivity, and complete antagonist properties in ligand-induced mitogenesis experiments. According to our schematic molecular model, the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm015522j
更新日期：2001-08-16 00:00:00
abstract：:Therapies based on activation of multiple Toll-like receptors (TLRs) may offer superior therapeutic profiles than that of single TLR activation. To discover new small molecules that could activate multiple TLRs, we performed a cell-based high-throughput screening of a small-molecule library based on TLR3-mediated NF-κ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00419
更新日期：2017-06-22 00:00:00
abstract：:In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01488
更新日期：2020-12-10 00:00:00
abstract：:Two isomeric 6-endo- and 6-exo-(3',4'-dihydroxyphenyl) derivatives (1 and 2) of 2-azabicyclo[2.2.2]octane were synthesized as semirigid analogues of dopamine (DA) to help evaluate the preferred conformation of dopamine at the uptake site of the presynaptic nerve terminal and at the DA receptor. Against the uptake of 0...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00345a004
更新日期：1982-03-01 00:00:00
abstract：:Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notably in coverage...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801514w
更新日期：2009-04-09 00:00:00
abstract：:The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300334d
更新日期：2012-09-13 00:00:00
abstract：:The maximum achievable accuracy of in silico models depends on the quality of the experimental data. Consequently, experimental uncertainty defines a natural upper limit to the predictive performance possible. Models that yield errors smaller than the experimental uncertainty are necessarily overtrained. A reliable es...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300131x
更新日期：2012-06-14 00:00:00
abstract：:Pan assay interference compounds (PAINS) have become a paradigm for compound classes that might cause artifacts in biological assays. PAINS-defining substructures are typically contained in larger compounds. We have systematically examined X-ray structures of protein-ligand complexes for compounds containing PAINS mot...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01780
更新日期：2018-02-08 00:00:00
abstract：:Closely related analogs of the 5-HT1A receptor agonist cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9- carboxamide (1, U93385) were synthesized and pharmacologically evaluated. 9-Carboxamide analogs with varied nitrogen substitution (R2) were synthesized, and their serotonergic activity was evaluate...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00004a018
更新日期：1995-02-17 00:00:00
abstract：:Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize select...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300248q
更新日期：2012-06-14 00:00:00
abstract：:Two separate libraries, prepared via parallel synthesis, were employed to identify low-molecular-weight SH2-targeted ligands for the Lck tyrosine protein kinase. These libraries were constructed to furnish non-amino acid analogues of the (1) Glu-Glu and (2) Ile residues of the Lck SH2 domain peptide ligand Ac-pTyr-Glu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990462r
更新日期：2000-03-23 00:00:00
abstract：:Learning and memory deficits in Alzheimer's disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (M...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300353r
更新日期：2012-08-09 00:00:00
abstract：:Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm7009233
更新日期：2007-12-13 00:00:00
abstract：:Novel substituted benzoyl benzoic acids and phenylacetic acids 1-14 have been synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes 1 and 2. The compounds turned out to be potent and selective human type 2 enzyme inhibitors, exhibiting IC(50) values in the nanomolar range. The phe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050728w
更新日期：2006-01-26 00:00:00
abstract：:A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. E...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201287w
更新日期：2012-01-26 00:00:00
abstract：:A series of thymidylate synthetase inhibitors was synthesized, some of which were potential irreversible inhibitors. 5-Formyl-2'-deoxyuridine (9) and its dithiolane derivative 11 were prepared by condensation of the bis(trimethylsilyl) derivative of 5-formyluracil dimethyl acetal and the protected chloro sugar followe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00229a010
更新日期：1976-07-01 00:00:00
abstract：:Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01766
更新日期：2017-03-23 00:00:00
abstract：:The binding constants of 15 phenothiazine derivatives to bovine serum albumin were obtained by a circular dichroic probe technique; The lipophilicity of the drugs, measured by a reversed-phase thin-layer technique using oleyl alcohol and methanol-water mixtures as the solvents, is expressed as RMw. The binding constan...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00213a022
更新日期：1977-03-01 00:00:00
abstract：:Several known alpha-amino acid analogues and a new compound, N-chloroacetylphosphoramidate, a carbamyl phosphate analogue, were screened as antitumor agents. All gave 50% growth inhibition of cultures of human epidemeroid carcinoma of the nasopharynx at dosage levels of 2-8 mug/ml while showing no activity against L12...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00213a026
更新日期：1977-03-01 00:00:00
abstract：:Basic derivatives of 6,7-dihydroindolo[1,7-ab][1]benzazepine and 6H-indolo[7,1-cd][1,5]benzoxazepine incorporating the imipramine basic side chain were synthesized and screened for antidepressant activity in mice. With few exceptions, the compounds unsubstituted at C-2 antagonized reserpine-induced ptosis and hypother...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00224a003
更新日期：1976-02-01 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 voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure-activity...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300623u
更新日期：2012-08-09 00:00:00
abstract：:The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3014597
更新日期：2013-03-14 00:00:00
abstract：:To produce reliable predictions of bioactive conformations is a major challenge in the field of structure-based inhibitor design and is a requirement for accurate binding free energy predictions with structure-based methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701218j
更新日期：2008-05-08 00:00:00
abstract：:The synthesis of a series of 2-, 3-, and 4-substituted benzylamine derivatives is described. These compounds were studied for their effect on experimental cardiac arrhythmias. Many of the derivatives, but in particular 2-(p-methoxyphenylethynyl)benzylamine (3d), alpha,alpha-dimethyl-4y(phenylethynyl)benzylamine (7a), ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00236a006
更新日期：1975-02-01 00:00:00
abstract：:Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked function of the structure of the starting ma...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020208q
更新日期：2002-10-10 00:00:00
abstract：:Membrane-bound aminopeptidase P (AP-P) participates in the degradation of bradykinin in several vascular beds. We have developed an inhibitor of AP-P called apstatin (1) (N-[(2S, 3R)-3-amino-2-hydroxy-4-phenyl-butanoyl]-L-prolyl-L-prolyl-L-al aninam ide); IC50,human = 2.9 microM. In the rat, apstatin can potentiate th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9805642
更新日期：1999-07-01 00:00:00
