Abstract:
:The modulation of the endocannabinoid system is emerging as a viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neurodegenerative disorders such as Alzheimer's disease, effectively preventing or slowing the progression of the disease. Hence, in the search for a more effective treatment for Alzheimer's disease, in this paper, the multitarget-directed ligand paradigm was applied to the design of carbamates able to simultaneously target the recently proposed endocannabinoid system and the classic cholinesterase system, and achieve effective dual FAAH/cholinesterase inhibitors. Among the two series of synthesized compounds, while some derivatives proved to be extremely potent on a single target, compounds 9 and 19 were identified as effective dual FAAH/ChE inhibitors, with well-balanced nanomolar activities. Thus, 9 and 19 might be considered as new promising candidates for Alzheimer's disease treatment.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Montanari S,Scalvini L,Bartolini M,Belluti F,Gobbi S,Andrisano V,Ligresti A,Di Marzo V,Rivara S,Mor M,Bisi A,Rampa Adoi
10.1021/acs.jmedchem.6b00609subject
Has Abstractpub_date
2016-07-14 00:00:00pages
6387-406issue
13eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章abstract::The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00143a007
更新日期:1981-11-01 00:00:00
abstract::A series of analogues of the analgesic dipeptide derivative H-Lys-Trp(NPS)-OMe has been designed to determine the influence of the (2-nitrophenyl)sulfenyl (NPS) moiety on the activity. The syntheses and antinociceptive effects of these analogues of general formula H-Lys-Trp(R)-OMe [R = phenylsulfenyl (PS) (9); R = (2-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00392a023
更新日期:1987-09-01 00:00:00
abstract::Two molecules with known growth hormone secretagogue (GHS) agonist activity were used as templates to computationally screen approximately 80000 compounds. A total of 108 candidate compounds were selected, and five of them were found to be active in the low-micromolar range in both cell-based and direct binding assays...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm040103i
更新日期:2004-08-12 00:00:00
abstract::Here we report on the design, synthesis, and biological characterization of novel κ opioid (KOP) receptor ligands of diphenethylamines. In opioid receptor binding and functional assays, the N-cyclobutylmethyl substituted derivative 4 (HS665) showed the highest affinity and selectivity for the KOP receptor and KOP agon...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm301258w
更新日期:2012-11-26 00:00:00
abstract::Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and oth...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01280
更新日期:2021-01-14 00:00:00
abstract::This series of reports describe the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. The compounds reported in this paper contain an additional phenyl ring, which has significantly improved the receptor affinity. The effect of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00166a017
更新日期:1990-04-01 00:00:00
abstract::A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00078a018
更新日期:1993-12-24 00:00:00
abstract::Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound als...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901230r
更新日期:2009-11-26 00:00:00
abstract::A series of novel 3-arylethynyltriazolyl ribonucleosides were synthesized and assessed for their anticancer activity on the drug-resistant pancreatic cancer cell line MiaPaCa-2. Among them, one compound exhibited potent apoptosis-inducing properties and anticancer activity against the pancreatic cancer model MiaPaCa-2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900960v
更新日期:2009-10-08 00:00:00
abstract::Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have rev...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01671
更新日期:2018-12-13 00:00:00
abstract::The effect of a variety of aryl substituents on the potency and selectivity of 19 analogues of 1,3-dipropyl-8-phenylxanthine as antagonists at A1- and A2-adenosine receptors in brain tissue was determined. The 4-sulfamoylphenyl and 4-carbamoylphenyl analogues are potent and somewhat selective for the A1 receptor. None...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00158a034
更新日期:1986-08-01 00:00:00
abstract::Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested agains...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm990467o
更新日期:2000-04-20 00:00:00
abstract::A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended dire...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm991131h
更新日期:2000-01-13 00:00:00
abstract::The natural dibenzylbutyrolactone type lignanolide (-)-arctigenin (2), an inhibitor of human immunodeficiency virus type-1 (HIV-1) replication in infected human cell systems, was found to suppress the integration of proviral DNA into the cellular DNA genome. In the present study 2 was tested with purified HIV-1 integr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950387u
更新日期:1996-01-05 00:00:00
abstract::Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizure...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00019a019
更新日期:1995-09-15 00:00:00
abstract::The 2'-chloro derivatives of etoposide and 4 beta-(arylamino)-4'-O-demethylpodophyllotoxins have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results showed that none of the compoun...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00083a009
更新日期:1992-03-06 00:00:00
abstract::Previous work has shown that incorporation of either 1-aminocyclohexanecarboxylic acid (Ac6c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonot...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0492709
更新日期:2005-02-10 00:00:00
abstract::Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00164a045
更新日期:1990-02-01 00:00:00
abstract::Quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) have been applied to elucidate the mechanisms of genotoxicity (SOSIP) of nitrofuran derivatives on Escherichia coli PQ37. The following equation was developed: log SOSIP = -33.1qc2 + 1.00 log P - 1.50Isat - 1.19MR - 0....
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00060a008
更新日期:1993-04-16 00:00:00
abstract::Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01569
更新日期:2021-01-28 00:00:00
abstract::A series of 62 diarylamidine derivatives was evaluated for their antiproteolytic activity. In all but two of the compounds one or both of the amidino-substituted aryl moieties was either an indole or an indole-like ring. The latter included indene, benzimidazole, benzofuran, benzol[beta]thiophene, and several other re...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00205a005
更新日期:1978-07-01 00:00:00
abstract::Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previous...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5011868
更新日期:2015-01-08 00:00:00
abstract::A series of quinone substrates were modeled into the active site of human DT-diaphorase and minimized. Correlation of these models with the substrate specificity k(cat)/K(m) provided insights into the structural requirements of quinone substrates. The W105, F106, and H194 residues can influence the position of the qui...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0104365
更新日期:2002-03-14 00:00:00
abstract::Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that co...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300810x
更新日期:2012-09-13 00:00:00
abstract::Lipophilicity/bioavailibility of Mn(III) N-alkylpyridylporphyrin-based superoxide dismutase (SOD) mimics has a major impact on their in vivo ability to suppress oxidative stress. Meta isomers are less potent SOD mimics than ortho analogues but are 10-fold more lipophilic and more planar. Enhanced lipophilicity contrib...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900576g
更新日期:2009-12-10 00:00:00
abstract::Ligand-induced stabilization of G-quadruplex structures formed by the human telomeric DNA is an active area of research. The compounds which stabilize the G-quadruplexes often lead to telomerase inhibition. Herein we present the results of interaction of new monomeric and dimeric ligands having 1,3-phenylene-bis(piper...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200860b
更新日期:2012-04-12 00:00:00
abstract::A series of 2-(1-piperazinyl)pyrazines was synthesized and evaluated for central serotonin-like activity. The most interesting member of the series, 6-chloro-2(1-piperazinyl)pyrazine (3a), had pharmacological properties characteristic of potent central serotoninmimetic activity and only weak peripheral serotoninmimeti...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00204a007
更新日期:1978-06-01 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::We present a comprehensive study of the performance of fast scoring functions for library docking using the program FlexX as the docking engine. Four scoring functions, among them two recently developed knowledge-based potentials, are evaluated on seven target proteins whose binding sites represent a wide range of siz...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0003992
更新日期:2001-03-29 00:00:00
abstract::There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01831
更新日期:2017-05-11 00:00:00