当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.

Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.

Abstract：

:A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Yang Q,Kang J,Zheng L,Wang XJ,Wan N,Wu J,Qiao Y,Niu P,Wang SQ,Peng Y,Wang Q,Yu W,Chang J

doi

10.1021/jm5012963

subject

Has Abstract

pub_date

2015-05-14 00:00:00

pages

3693-703

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Synthesis of β-Carboline-Based N-Heterocyclic Carbenes and Their Antiproliferative and Antimetastatic Activities against Human Breast Cancer Cells.

    abstract：:A series of novel β-carboline-based N-heterocyclic carbenes was prepared via Mannich reaction between methyl 1-(dimethoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate, formaldehyde, and primary amines. All compounds were evaluated for their antiproliferative activity using human breast cancer and lung cancer cell lines...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00016

    authors： Dighe SU,Khan S,Soni I,Jain P,Shukla S,Yadav R,Sen P,Meeran SM,Batra S

    更新日期：2015-04-23 00:00:00

  • The cis-4-amino-L-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues.

    abstract：:Endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH(2)) is an endogenous tetrapeptide that combines potency and efficacy with high affinity and selectivity toward the μ opioid receptor, the most responsible for analgesic effects in the central nervous system. The presence of the Pro(2) represents a crucial factor for the ligand s...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm201402v

    authors： Mollica A,Pinnen F,Stefanucci A,Feliciani F,Campestre C,Mannina L,Sobolev AP,Lucente G,Davis P,Lai J,Ma SW,Porreca F,Hruby VJ

    更新日期：2012-04-12 00:00:00

  • Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration.

    abstract：:N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00029

    authors： Lin H,Long JZ,Roche AM,Svensson KJ,Dou FY,Chang MR,Strutzenberg T,Ruiz C,Cameron MD,Novick SJ,Berdan CA,Louie SM,Nomura DK,Spiegelman BM,Griffin PR,Kamenecka TM

    更新日期：2018-04-12 00:00:00

  • Gonadotropin-releasing hormone antagonists with N omega-triazolylornithine, -lysine, or -p-aminophenylalanine residues at positions 5 and 6.

    abstract：:In order to be used as fertility regulators in humans, gonadotropin releasing hormone (GnRH) antagonists must be extremely potent and long acting and exhibit negligible side effects such as stimulating histamine release. To this aim, we have recently synthesized a series of analogues with the standard Ac-DNal1-DCpa2-D...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00101a003

    authors： Rivier J,Porter J,Hoeger C,Theobald P,Craig AG,Dykert J,Corrigan A,Perrin M,Hook WA,Siraganian RP

    更新日期：1992-11-13 00:00:00

  • Antiinflammatory activity of a series of substituted 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-diones.

    abstract：:A series of substituted analogues based on the novel 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-dione ring system have been synthesized and shown to exhibit antiinflammatory activity in the adjuvant-induced arthritis rat model (AAR). The activity exhibited by the pyrimidopurinediones in this model of chroni...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00125a029

    authors： Kaminski JJ,Solomon DM,Conn DJ,Wong SC,Chiu PJ,Massa T,Siegel MI,Watnick AS

    更新日期：1989-05-01 00:00:00

  • Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging.

    abstract：:We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200536d

    authors： Andrés JI,De Angelis M,Alcázar J,Iturrino L,Langlois X,Dedeurwaerdere S,Lenaerts I,Vanhoof G,Celen S,Bormans G

    更新日期：2011-08-25 00:00:00

  • Design, synthesis, and biological evaluation of theranostic vitamin-linker-taxoid conjugates.

    abstract：:Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-PET radiotracer (1) or a fluorescence probe (2) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of 2 in biotin-receptor positive (BR+) canc...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm5019115

    authors： Vineberg JG,Wang T,Zuniga ES,Ojima I

    更新日期：2015-03-12 00:00:00

  • Novel Strategies To Activate the Dopamine D1 Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation.

    abstract：:The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.8b01767

    authors： Hall A,Provins L,Valade A

    更新日期：2019-01-10 00:00:00

  • Phototoxicity of chlorpromazine.

    abstract：:The constitution of chlorpromazine has been studied in the context of its phototoxicity. Electron transfer from the side chain to the aromatic nucleus of the drug contributes to its instability to light. Even without the side chain, however, chlorophenothiazines appear to be very photolabile, so that it is unlikely th...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00188a016

    authors： Bunce NJ,Kumar Y,Ravanal L

    更新日期：1979-02-01 00:00:00

  • New COX-2/5-LOX inhibitors: apoptosis-inducing agents potentially useful in prostate cancer chemotherapy.

    abstract：:The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0407761

    authors： Pommery N,Taverne T,Telliez A,Goossens L,Charlier C,Pommery J,Goossens JF,Houssin R,Durant F,Hénichart JP

    更新日期：2004-12-02 00:00:00

  • On the histone lysine methyltransferase activity of fungal metabolite chaetocin.

    abstract：:Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally rela...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm401063r

    authors： Cherblanc FL,Chapman KL,Reid J,Borg AJ,Sundriyal S,Alcazar-Fuoli L,Bignell E,Demetriades M,Schofield CJ,DiMaggio PA Jr,Brown R,Fuchter MJ

    更新日期：2013-11-14 00:00:00

  • Nonsymmetrical bipiperidyls as inhibitors of vesicular acetylcholine storage.

    abstract：:Introduction of a nitrogen atom into the cyclohexane ring of 2-(4-phenylpiperidinyl)cyclohexanol (vesamicol, AH5183) yielded two positional isomers, 5-azavesamicol (5, prezamicol) and 4-azavesamicol (6, trozamicol). As inhibitors of vesicular acetylcholine transport, 5 and 6 were found to be 147 and 85 times less pote...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00060a005

    authors： Efange SM,Khare A,Parsons SM,Bau R,Metzenthin T

    更新日期：1993-04-16 00:00:00

  • Amide, urea, and carbamate analogues of the muscarinic agent [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride.

    abstract：:A series of amide, urea, and carbamate analogues of the muscarinic (M1) ganglionic stimulant [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride (McN-A-343; 1) was prepared. The C1-methyl-substituted carbamates 8-11 were resolved into the enantiomers. In order to investigate the ganglionic stimu...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00093a011

    authors： Nilsson BM,Vargas HM,Hacksell U

    更新日期：1992-07-24 00:00:00

  • Selective inhibitors of monoamine oxidase. 2. Arylamide SAR.

    abstract：:Monoamine oxidase (MAO) exists in two forms distinguishable by substrate specificity. Inhibition of MAO A is believed to be responsible for the antidepressant activity of MAO inhibitors. A group of N-arylacetamides are highly specific inhibitors of MAO A, some with IC50 values in the 10-100 nM range. The requirements ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00039a021

    authors： Harfenist M,Joyner CT,Mize PD,White HL

    更新日期：1994-06-24 00:00:00

  • Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging.

    abstract：:We have reported that [methyl- (11)C] (3 R,5 R)-5-(3-methoxyphenyl)-3-[(R)-1-phenylethylamino]-1-(4-trifluoromethylphenyl)pyrrolidin-2-one ([(11)C] 8, [(11)C]MePPEP) binds with high selectivity to cannabinoid type-1 (CB 1) receptors in monkey brain in vivo. We now describe the synthesis of 8 and four analogues, namely...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800416m

    authors： Donohue SR,Krushinski JH,Pike VW,Chernet E,Phebus L,Chesterfield AK,Felder CC,Halldin C,Schaus JM

    更新日期：2008-09-25 00:00:00

  • Molecular and conformational determinants of pituitary adenylate cyclase-activating polypeptide (PACAP) for activation of the PAC1 receptor.

    abstract：:PAC1 receptor is abundant in the CNS and plays an important role in neuronal survival. To identify the molecular determinants and the conformational components responsible for the activation of the PAC1 receptor, we performed a SAR study focusing on the N-terminal domain of its endogenous ligand, PACAP. This approach ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900291j

    authors： Bourgault S,Vaudry D,Ségalas-Milazzo I,Guilhaudis L,Couvineau A,Laburthe M,Vaudry H,Fournier A

    更新日期：2009-05-28 00:00:00

  • Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.

    abstract：:New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00760

    authors： Vidadala RS,Rivas KL,Ojo KK,Hulverson MA,Zambriski JA,Bruzual I,Schultz TL,Huang W,Zhang Z,Scheele S,DeRocher AE,Choi R,Barrett LK,Siddaramaiah LK,Hol WG,Fan E,Merritt EA,Parsons M,Freiberg G,Marsh K,Kempf DJ,Ca

    更新日期：2016-07-14 00:00:00

  • Cross-linking and sequence-specific alkylation of DNA by aziridinylquinones. 3. Effects of alkyl substituents.

    abstract：:The cytotoxicities and DNA cross-linking abilities of several alkyl-substituted diaziridinylquinones have been investigated. The cytotoxicities were determined in DT-diaphorase-rich (H460 and HT29) and -deficient (H596 and BE) cell lines. It was shown that the cytotoxicities in these cell lines correlated with the rel...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm991007y

    authors： Hargreaves RH,O'Hare CC,Hartley JA,Ross D,Butler J

    更新日期：1999-06-17 00:00:00

  • Analgesic and tranquilizing activity of 5,8-disubstituted 2-aminomethyl-3,4-dihydronaphthalenes.

    abstract：:Interesting analgesic activity approaching that of meperidine and codeine was observed in standard animal models for 8-chloro-3,4-dihydro-5-methoxy-2-pyrrolidinomethylnaphthalene (compound 7). This compound was orally effective and its analgesic activity was not reversed by the opiate antagonist, naloxone. A limited n...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00201a004

    authors： Welch WM,Plattner JJ,Stratten WP,Harbert CA

    更新日期：1978-03-01 00:00:00

  • (Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators.

    abstract：:The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 overexpression is thought to contribute to the development of cancer. We recently reported a series of (bis)guanidines and (bis)biguani...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100217a

    authors： Sharma SK,Wu Y,Steinbergs N,Crowley ML,Hanson AS,Casero RA,Woster PM

    更新日期：2010-07-22 00:00:00

  • Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.

    abstract：:As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate subst...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b01249

    authors： Schiffler MA,Antonysamy S,Bhattachar SN,Campanale KM,Chandrasekhar S,Condon B,Desai PV,Fisher MJ,Groshong C,Harvey A,Hickey MJ,Hughes NE,Jones SA,Kim EJ,Kuklish SL,Luz JG,Norman BH,Rathmell RE,Rizzo JR,Seng TW,Thi

    更新日期：2016-01-14 00:00:00

  • Design, synthesis, and activity of analogues of phosphinothricin as inhibitors of glutamine synthetase.

    abstract：:A new group of potent inhibitors of glutamine synthetase was designed and synthesized. The X-ray structure of bacterial glutamine synthetase complexed with phosphinothricin was used for computer-aided structure-based design of the inhibitors, in which the methyl group of phosphinothricin was chosen as the modification...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm050474e

    authors： Berlicki Ł,Obojska A,Forlani G,Kafarski P

    更新日期：2005-10-06 00:00:00

  • Synthesis and copper-dependent antimycoplasmal activity of amides and amidines derived from 2-amino-1,10-phenanthroline.

    abstract：:A series of both aliphatic and aromatic amides and aromatic amidines derived from 2-amino-1,10-phenanthroline (3) according to the Topliss scheme were synthesized and subsequently tested for antimycoplasmal potency. Although the compounds themselves showed no activity, in the presence of a nontoxic copper concentratio...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00107a045

    authors： de Zwart MA,Bastiaans HM,van der Goot H,Timmerman H

    更新日期：1991-03-01 00:00:00

  • Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists.

    abstract：:Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030490g

    authors： Blum CA,Zheng X,De Lombaert S

    更新日期：2004-04-22 00:00:00

  • Conformational analysis of the prototype nonclassical cannabinoid CP-47,497, using 2D NMR and computer molecular modeling.

    abstract：:In an effort to determine the stereochemical requirements for pharmacological activity among the series of nonclassical cannabinoids synthesized at Pfizer, we have studied the conformational properties of the parent bicyclic analog CP-47,497. For this study, we have used a combination of solution NMR and theoretical c...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00036a006

    authors： Xie XQ,Yang DP,Melvin LS,Makriyannis A

    更新日期：1994-05-13 00:00:00

  • Design and synthesis of 4,5-diphenyl-4-isoxazolines: novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity.

    abstract：:4,5-Diphenyl-4-isoxazolines (13a-k) possessing a variety of substituents (H, F, MeS, MeSO2) at the para position of one of the phenyl rings were synthesized for evaluation as analgesic and selective cyclooxygenase-2 (COX-2) inhibitory antiinflammatory (AI) agents. Although the 4,5-phenyl-4-isoxazolines (13a-d,f), whic...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0101287

    authors： Habeeb AG,Praveen Rao PN,Knaus EE

    更新日期：2001-08-30 00:00:00

  • Highly potent, orally active diester macrocyclic human renin inhibitors.

    abstract：:Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the se...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00099a004

    authors： Weber AE,Steiner MG,Krieter PA,Colletti AE,Tata JR,Halgren TA,Ball RG,Doyle JJ,Schorn TW,Stearns RA

    更新日期：1992-10-16 00:00:00

  • Synthesis of (R)-(-)- and (S)-(+)-4-fluorodeprenyl and (R)-(-)- and (S)-(+)-[N-11C-methyl]-4-fluorodeprenyl and positron emission tomography studies in baboon brain.

    abstract：:(R)-(-)- and (S)-(+)-alpha-methyl-beta-4-(fluorophenyl)-N-methyl-N- propynylethylamine [R)-(-)- and (S)-(+)-4-fluorodeprenyl) were synthesized via the reaction of 4-fluorobenzaldehyde with nitroethane followed by reduction with lithium aluminum hydride to produce racemic 4-fluoroamphetamine, which was resolved by recr...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00169a034

    authors： Plenevaux A,Dewey SL,Fowler JS,Guillaume M,Wolf AP

    更新日期：1990-07-01 00:00:00

  • Synthesis and biological evaluation of the methyl esters of (+)-12-fluoro-13,14-dihydroprostaglandin F2alpha and (+)-15-epi-12-fluoro-13,14-dihydroprostaglandin F2alpha.

    abstract：:(+)-12-Fluoro-13,14-dihydroprostaglandin F2alpha methyl ester (2a) and (+)-15-epi-12-fluoro-13,14-dihydroprostaglandin F2alpha methyl ester (2b) were prepared from the readily available (-)-7-fluorospiro[bicyclo[2.2.1]hept-5-ene-2,2'-[1,3]dioxolane]-7-methanol (3). Fluoroprostaglandins 2a and 2b possess truly signific...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00139a014

    authors： Grieco PA,Takigawa T

    更新日期：1981-07-01 00:00:00

  • Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.

    abstract：:Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm990365y

    authors： Fisher MJ,Arfstan AE,Giese U,Gunn BP,Harms CS,Khau V,Kinnick MD,Lindstrom TD,Martinelli MJ,Mest HJ,Mohr M,Morin JM Jr,Mullaney JT,Nunes A,Paal M,Rapp A,Rühter G,Ruterbories KJ,Sall DJ,Scarborough RM,Schotten T,S

    更新日期：1999-11-18 00:00:00