Abstract：
:On the basis of docking studies carried out using the recently published cannabinoid receptor models,35 new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a Ki of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl)quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with Ki of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (Ki(CB1)/Ki(CB2) ratio greater than 303). Moreover, the [35S]GTPgamma binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Manera C,Benetti V,Castelli MP,Cavallini T,Lazzarotti S,Pibiri F,Saccomanni G,Tuccinardi T,Vannacci A,Martinelli A,Ferrarini PLdoi
10.1021/jm0603466subject
Has Abstractpub_date
2006-10-05 00:00:00pages
5947-57issue
20eissn
0022-2623issn
1520-4804journal_volume
49pub_type
杂志文章abstract：:A series of analogues of 4,5-bis(((N-methylcarbamoyl)oxy)methyl)-1-methyl-2-(methylthio)-im idazole (1, carmethizole) were synthesized. The chemical reactivities of the analogues (as electrophiles) were evaluated and related to the antitumor activity (in vivo and in vitro). Changes in the alkylthio moiety had a signif...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00075a017
更新日期：1993-11-12 00:00:00
abstract：:In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0603623
更新日期：2006-11-02 00:00:00
abstract：:1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprot...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01101
更新日期：2015-10-22 00:00:00
abstract：:Analogues of the antimycotic allylamine terbinafine were prepared in which the naphthalene and the tert-butyl-acetylene moieties were preserved, but the spacer between these two groups was varied, and the antifungal activity of the new compounds was evaluated. All modifications of the original spacer such as reduction...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00031a010
更新日期：1994-03-04 00:00:00
abstract：:S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules wit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00928
更新日期：2015-12-10 00:00:00
abstract：:In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using mo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801385d
更新日期：2009-04-23 00:00:00
abstract：:alpha-Fluoromethyl amino acids are enzyme-activated irreversible inhibitors of amino acid decarboxylases. Aromatic L-amino acid decarboxylase (AADC) is the enzyme responsible for the final step in the biosynthesis of both dopamine and serotonin via decarboxylation of L-dopa and 5-hydroxy-L-tryptophan, respectively. Ou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00055a001
更新日期：1993-02-05 00:00:00
abstract：:2-(p-Nitrophenyl)-4-isopropylmorphine (V), an analog of 1-(p-nitrophenyl)-2-isopropylaminoethanol (INPEA, I) in which the OCHCHN chain of I is locked in a morpholine ring, loses the beta-receptor blocking activity of I on various isolated preparations. The same ineffectiveness is observed in the O-methyl (II), N-methy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00242a016
更新日期：1975-08-01 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：:Syntheses of 2-fluoroformycin [7-amino-5-fluoro-3-(beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine] (2b) and 2-aminoformycin [5,7-diamino-3-(beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine] (2c) are described. Cytotoxicity data are given for 2b and 2c alone as well as with added pentostatin. Kinetic parameters for adeno...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00149a033
更新日期：1985-11-01 00:00:00
abstract：:The quinazoline class was exploited to search for a new translocator protein (TSPO) fluorescent probe endowed with improved affinity and residence time (RT). Computational studies on an "in-house" collection of quinazoline derivatives, featuring highly steric demanding groups at the amide nitrogen, suggested that, des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01031
更新日期：2017-09-28 00:00:00
abstract：:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimiz...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00379
更新日期：2016-10-13 00:00:00
abstract：:A novel series of 2- and 3-substituted 1,8-dihydroxy-9(10H)-anthracenones were synthesized and tested for their inhibitory activity against 5-lipoxygenase (5-LO) in bovine polymorphonuclear leukocytes and the growth of human keratinocytes. Structure-activity relationships are discussed with respect to the following re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00037a017
更新日期：1994-05-27 00:00:00
abstract：:New transition-state analogues bearing C-termini derived from alpha-mercaptoalkanoic acids, esters, and amides were prepared and evaluated as inhibitors of human renin. Addition of alpha-mercaptoalkanoate esters to a chiral Boc-amino epoxide intermediate led ultimately to the target [(2R,3S)-3-(BocPheHis-amino)-4-cycl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00093a009
更新日期：1992-07-24 00:00:00
abstract：:In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401992e
更新日期：2014-04-24 00:00:00
abstract：:Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5019719
更新日期：2015-02-26 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：:The importance of steric factors in quantitative structure-activity relationships involving steroid hormones is discussed. a variety of steric parameters, such as parachlor, molecular volume, van der Waals volume, and including difference and squared steric terms, is explored in an attempt to find preferred forms for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00228a002
更新日期：1976-06-01 00:00:00
abstract：:Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm2001508
更新日期：2011-07-14 00:00:00
abstract：:Benzimidazoles carrying the 2-hydroxy-3-(isopropylamino)propoxy side chain at either the C-4 or C-5 ring positions were synthesized and investigated for beta-adrenergic blocking activity. Both compounds demonstrated beta2 selectivity when evaluated in guinea pig atrial and tracheal preparations. The C-4 isomer was 17 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00188a019
更新日期：1979-02-01 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：: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：:In an attempt to synthesize pentamidine-aplysinopsin hybrid molecule 25, a lead molecule 8 (containing Z-configured aplysinopsin moiety) was identified for antileishmanial activity. Optimization of lead 8 provided 24 (containing E-configured aplysinopsin) possessing 10 times more activity and 401-fold less toxicity th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900564x
更新日期：2009-10-08 00:00:00
abstract：:The ability of a series of substituted kynurenic acids, thienopyridinonecarboxylic acids, and related compounds to inhibit the binding of nerve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated in a radioligand binding assay that utilized a biotinylated derivative of the extracellular domain of p75 NGFR...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00022a008
更新日期：1995-10-27 00:00:00
abstract：:A series of aryl bicyclic analogs of succinimide and glutarimide was prepared and evaluated for CNS depressant activity. The 8a-aryl-3,4,6,7,8,8a-hexahydro-2H-pyrrolo[2,1-beta][1,3]oxazin-6-ones possessed the best overall spectrum of activity relative to the standard agents glutethimide and phenobarbital. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00225a023
更新日期：1976-03-01 00:00:00
abstract：:Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0309452
更新日期：2004-02-12 00:00:00
abstract：:A group of nitro and amino derivatives of lucanthone was prepared and tested for antitumor activity. Reaction of 1-chloro-4-methyl-7-nitrothioxanthenone and N,N-diethylethylenediamine gave the 7-amino analogue (11) directly, accompanied by 7-amino-1-chloro-4-methylthioxanthenone. The antitumor activity of 11 was infer...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00345a020
更新日期：1982-03-01 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：:Primaquine (I) has been extensively used in combination with other drugs in the radical cure of relapsing malaria as well as for prophylaxis or the interruption of transmission. This, coupled with the activity data reported for 4-methylprimaquine (II), has led to the synthesis of a series of 14 4-substituted analogues...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00219a003
更新日期：1977-09-01 00:00:00
abstract：:Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compoun...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501285x
更新日期：2015-01-22 00:00:00
