当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Structure-Activity Relationship, Drug Metabolism and Pharmacokinetics Properties Optimization, and in Vivo Studies of New Brain Penetrant Triple T-Type Calcium Channel Blockers.

Structure-Activity Relationship, Drug Metabolism and Pharmacokinetics Properties Optimization, and in Vivo Studies of New Brain Penetrant Triple T-Type Calcium Channel Blockers.

Abstract：

:Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Siegrist R,Pozzi D,Jacob G,Torrisi C,Colas K,Braibant B,Mawet J,Pfeifer T,de Kanter R,Roch C,Kessler M,Moon R,Corminboeuf O,Bezençon O

doi

10.1021/acs.jmedchem.6b01356

subject

Has Abstract

pub_date

2016-12-08 00:00:00

pages

10661-10675

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.

    abstract：:We have previously found that the 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazolines can function as potent and selective inhibitors of platelet-derived growth factor receptor (PDGFR) phosphorylation. A series of highly potent, specific, orally active, small molecule kinase inhibitors directed aga...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm020143r

    authors： Pandey A,Volkots DL,Seroogy JM,Rose JW,Yu JC,Lambing JL,Hutchaleelaha A,Hollenbach SJ,Abe K,Giese NA,Scarborough RM

    更新日期：2002-08-15 00:00:00

  • Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide: synthesis, reactivity, and mechanistic analysis.

    abstract：:The neutral endopeptidase inhibitor (2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic acid 2 is metabolized to acyl glucuronide 3. Unprecedentedly, at pH 7.4, 3 does not undergo the O-acyl migration characteristic of acyl glucuronides but rapid, eliminative cyclization (t1/2 at 37...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0706766

    authors： Meng X,Maggs JL,Pryde DC,Planken S,Jenkins RE,Peakman TM,Beaumont K,Kohl C,Park BK,Stachulski AV

    更新日期：2007-11-29 00:00:00

  • Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates.

    abstract：:We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm058213s

    authors： Gangjee A,Zeng Y,McGuire JJ,Kisliuk RL

    更新日期：2005-08-11 00:00:00

  • Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.

    abstract：:The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501266w

    authors： Epstein O,Bryan MC,Cheng AC,Derakhchan K,Dineen TA,Hickman D,Hua Z,Human JB,Kreiman C,Marx IE,Weiss MM,Wahl RC,Wen PH,Whittington DA,Wood S,Zheng XM,Fremeau RT Jr,White RD,Patel VF

    更新日期：2014-12-11 00:00:00

  • Synthesis and biological activity of CCK heptapeptide analogues. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo.

    abstract：:A series of modifications of the CCK7 analogue (des-NH2)Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-Phe-NH2 was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppressant activity in rats. Several conformationally rest...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00094a001

    authors： Holladay MW,Bennett MJ,Tufano MD,Lin CW,Asin KE,Witte DG,Miller TR,Bianchi BR,Nikkel AL,Bednarz L

    更新日期：1992-08-07 00:00:00

  • Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift.

    abstract：:Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and poten...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.0c00982

    authors： Thorat SA,Lee Y,Jung A,Ann J,Ahn S,Baek J,Zuo D,Do N,Jeong JJ,Blumberg PM,Esch TE,Turcios NA,Pearce LV,Ha HJ,Yoo YD,Hong S,Choi S,Lee J

    更新日期：2021-01-14 00:00:00

  • Synthesis and biological characterization of pyridohomotropanes. Structure-activity relationships of conformationally restricted nicotinoids.

    abstract：:The recently discovered nicotinic agonist pyrido[3,4-b]norhomotropane [corrected] (PHT) as well as its N-methyl and 2'-methyl derivatives (syntheses reported herein) were compared with nicotine, nornicotine, and anatoxin a in a series of in vitro and in vivo assays. The results reveal that PHT possesses activity compa...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00398a004

    authors： Kanne DB,Abood LG

    更新日期：1988-03-01 00:00:00

  • Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model.

    abstract：:The linear interaction energy method with continuum electrostatics (LIECE) is evaluated in depth on five kinases. The two multiplicative coefficients for the van der Waals energy and electrostatic free energy are shown to be transferable among different kinases. Moreover, good enrichment factors are obtained for a lib...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm070654j

    authors： Kolb P,Huang D,Dey F,Caflisch A

    更新日期：2008-03-13 00:00:00

  • Hydrophilic pyrazine dyes as exogenous fluorescent tracer agents for real-time point-of-care measurement of glomerular filtration rate.

    abstract：:Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine-2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutra...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200257k

    authors： Rajagopalan R,Neumann WL,Poreddy AR,Fitch RM,Freskos JN,Asmelash B,Gaston KR,Galen KP,Shieh JJ,Dorshow RB

    更新日期：2011-07-28 00:00:00

  • 8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors.

    abstract：:3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine V11294 (1) has been identified as a lead structure, which selectively inhibits human lung PDE4 (436 nM) and is also active in a number of in vitro and in vivo models of inflammation. Here we describe the synthesis and pharmacology of a series of highly potent 8...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030603w

    authors： Whitehead JW,Lee GP,Gharagozloo P,Hofer P,Gehrig A,Wintergerst P,Smyth D,McCoull W,Hachicha M,Patel A,Kyle DJ

    更新日期：2005-02-24 00:00:00

  • A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor.

    abstract：:The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conf...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00972

    authors： Borsari C,Rageot D,Dall'Asen A,Bohnacker T,Melone A,Sele AM,Jackson E,Langlois JB,Beaufils F,Hebeisen P,Fabbro D,Hillmann P,Wymann MP

    更新日期：2019-09-26 00:00:00

  • Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase.

    abstract：:Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with a nonsubstrate analog inhibitor. Given the active site simil...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00977

    authors： Luciani R,Saxena P,Surade S,Santucci M,Venturelli A,Borsari C,Marverti G,Ponterini G,Ferrari S,Blundell TL,Costi MP

    更新日期：2016-10-13 00:00:00

  • Chlorogenic acid derivatives with alkyl chains of different lengths and orientations: potent alpha-glucosidase inhibitors.

    abstract：:Alpha-glucosidases play important roles in the digestion of carbohydrates and biosynthesis of viral envelope glycoproteins. Inhibitors of alpha-glucosidase are promising candidates for the development of antitype II diabetics and anti-AIDS drugs. Here, we report the synthesis and alpha-glucosidase inhibitory activity ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800621x

    authors： Ma CM,Hattori M,Daneshtalab M,Wang L

    更新日期：2008-10-09 00:00:00

  • Structure and solution conformation of the cytostatic cyclic tetrapeptide WF-3161, cyclo[L-leucyl-L-pipecolyl-L-(2-amino-8-oxo-9, 10-epoxydecanoyl)-D-phenylalanyl].

    abstract：:The sequence and configuration of amino acids in the cytostatic cyclic tetrapeptide WF-3161 are established as cyclo(L-Leu-L-Pip-L-Aoe-D-Phe) where Pip = pipecolic acid and Aoe = 2-amino-8-oxo-9,10-epoxydecanoic acid. In chloroform, WF-3161 adopts a conformation with a possible gamma-turn between Leu NH and Aoe C = O ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00161a046

    authors： Kawai M,Pottorf RS,Rich DH

    更新日期：1986-11-01 00:00:00

  • Synthesis, biological activity, and molecular modeling investigation of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as human A(3) adenosine receptor antagonists.

    abstract：:A new series of pyrazolotriazolopyrimidines bearing different substitutions on the phenylcarbamoyl moieties at the N5 position, being highly potent and selective human A(3) adenosine receptor antagonists, is described. The compounds represent an extension and an improvement of our previous work on this class of compou...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0109614

    authors： Baraldi PG,Cacciari B,Moro S,Spalluto G,Pastorin G,Da Ros T,Klotz KN,Varani K,Gessi S,Borea PA

    更新日期：2002-02-14 00:00:00

  • Diverse, high-quality test set for the validation of protein-ligand docking performance.

    abstract：:A procedure for analyzing and classifying publicly available crystal structures has been developed. It has been used to identify high-resolution protein-ligand complexes that can be assessed by reconstructing the electron density for the ligand using the deposited structure factors. The complexes have been clustered a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm061277y

    authors： Hartshorn MJ,Verdonk ML,Chessari G,Brewerton SC,Mooij WT,Mortenson PN,Murray CW

    更新日期：2007-02-22 00:00:00

  • (1-Amino-2-propenyl) phosphonic acid, an inhibitor of alanine racemase and D-alanine:D-alanine ligase.

    abstract：:DL-(1-Amino-2-propenyl)phosphonic acid was synthesized through the sequential oxidation, sulfoxide elimination, and deprotection of diphenyl [1-[(benzyloxycarbonyl)amino]-3-(phenylthio)propyl] phosphonate. This analogue of vinylglycine is a strong inhibitor of the alanine racemases from Pseudomonas aeruginosa and Stre...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00154a024

    authors： Vo-Quang Y,Carniato D,Vo-Quang L,Lacoste AM,Neuzil E,Le Goffic F

    更新日期：1986-04-01 00:00:00

  • Synthesis and biological activity of potential antimetabolites of L-fucose.

    abstract：:6-Substituted 6-deoxy-L-galactose (L-fucose) derivatives were synthesized as potential antimetabolites of L-fucose. The cytotoxic effects of these compounds were evaluated on P388 leukemia cells in culture. The L-fucose analogues which showed the most potent growth inhibition were the sulfonyl ester, bromo, and iodo d...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00194a017

    authors： May JA Jr,Sartorelli AC

    更新日期：1979-08-01 00:00:00

  • Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE).

    abstract：:Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060154a

    authors： Hanessian S,Yang G,Rondeau JM,Neumann U,Betschart C,Tintelnot-Blomley M

    更新日期：2006-07-27 00:00:00

  • Discovery of novel and long acting muscarinic acetylcholine receptor antagonists.

    abstract：:High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800634k

    authors： Jin J,Wang Y,Shi D,Wang F,Davis RS,Jin Q,Fu W,Foley JJ,Webb EF,Dehaas CJ,Berlanga M,Burman M,Sarau HM,Morrow DM,Rao P,Kallal LA,Moore ML,Rivero RA,Palovich M,Salmon M,Belmonte KE,Busch-Petersen J

    更新日期：2008-08-28 00:00:00

  • Ru(II) Compounds: Next-Generation Anticancer Metallotherapeutics?

    abstract：:Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically imaging, and therapeutics applications. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.7b01689

    authors： Thota S,Rodrigues DA,Crans DC,Barreiro EJ

    更新日期：2018-07-26 00:00:00

  • A marked change of receptor affinity of the 2-methyl-5-(3-hydroxyphenyl)morphans upon attachment of an (E)-8-benzylidene moiety: synthesis and evaluation of a new class of sigma receptor ligands.

    abstract：:The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding en...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00045a022

    authors： Bertha CM,Mattson MV,Flippen-Anderson JL,Rothman RB,Xu H,Cha XY,Becketts K,Rice KC

    更新日期：1994-09-16 00:00:00

  • Para-substituted Phe3 deltorphin analogues: enhanced selectivity of halogenated derivatives for delta opioid receptor sites.

    abstract：:The delta-selective opioid peptide deltorphin C(H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) (DEL C) was modified by para-substitution of Phe3 with halogens (F, Cl, Br, I), amino, or nitro groups. The bioactive potencies in peripheral tissues and brain receptor selectivities of these analogues depended upon the particular sub...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00103a001

    authors： Salvadori S,Bianchi C,Lazarus LH,Scaranari V,Attila M,Tomatis R

    更新日期：1992-12-11 00:00:00

  • Cytotoxic activity of metal complexes of biogenic polyamines: polynuclear platinum(II) chelates.

    abstract：:Several polynuclear Pt(II) chelates with biogenic polyamines were synthesized and screened for their potential antiproliferative and cytotoxic activity in different human cancer cell lines. To gather information regarding the structure-activity relationships underlying their biological activity, the complexes studied ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0311238

    authors： Teixeira LJ,Seabra M,Reis E,da Cruz MT,de Lima MC,Pereira E,Miranda MA,Marques MP

    更新日期：2004-05-20 00:00:00

  • (1,3-Dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones. A series of novel central nervous system depressants.

    abstract：:A series of novel (1,3-dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones was synthesized. Pharmacological evaluation of these compounds demonstrated central nervous system depressant activity, potential anticonvulsant properties, and a low order of acute toxicity. In addition, selected compounds showed potential antipsyc...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00377a003

    authors： Butler DE,Wise LD,DeWald HA

    更新日期：1984-11-01 00:00:00

  • Structurally specific binding of halogenated biphenyls to thyroxine transport protein.

    abstract：:Prealbumin is a major thyroxine binding protein in blood that has been well studied crystallographically and has also been proposed as a model for the thyroxine nuclear receptor in tissue. The high-affinity T4 binding site in prealbumin gave a linear plot on Scatchard analysis. The interactions of selected polychlorin...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00155a010

    authors： Rickenbacher U,McKinney JD,Oatley SJ,Blake CC

    更新日期：1986-05-01 00:00:00

  • A novel decoy that interrupts G93A-superoxide dismutase gain of interaction with malate dehydrogenase improves survival in an amyotrophic lateral sclerosis cell model.

    abstract：:Human G93A-superoxide dismutase-1 (G93AhSOD1) mutation causes amyotrophic lateral sclerosis (ALS) in rodents and humans. Recent observations indicate gain of interaction of G93AhSOD1 with cytosolic malate dehydrogenase (MDH1) and subsequent impairment in the malate aspartate shuttle which is vital to neurons. Using fl...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900631m

    authors： Mali Y,Zisapel N

    更新日期：2009-09-10 00:00:00

  • Fuplatin: An Efficient and Low-Toxic Dual-Prodrug.

    abstract：:As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of "dual-prodrug" by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10-17, named Fuplatin...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00128

    authors： Zhang R,Song XQ,Liu RP,Ma ZY,Xu JY

    更新日期：2019-05-09 00:00:00

  • Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.

    abstract：:NAD+-dependent histone deacetylases, sirtuins, cleave acetyl groups from lysines of histones and other proteins to regulate their activity. Identification of potent selective inhibitors would help to elucidate sirtuin biology and could lead to useful therapeutic agents. NAD+ has an adenosine moiety that is also presen...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060118b

    authors： Trapp J,Jochum A,Meier R,Saunders L,Marshall B,Kunick C,Verdin E,Goekjian P,Sippl W,Jung M

    更新日期：2006-12-14 00:00:00

  • Synthesis and antineoplastic activity of phenyl-substituted benzenesulfonylhydrazones of 2-pyridinecarboxyaldehyde 1-oxide.

    abstract：:A variety of derivatives of 2-pyridinecarboxaldehyde 1-oxide benzenesulfonylhydrazone, containing substituents on the benzene or pyridine rings as well as on the nitrogen atom which is bonded directly to the sulfonyl group, have been synthesized. The antineoplastic activity of these compounds has been assessed in mice...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00180a010

    authors： Loh W,Cosby LA,Sartorelli AC

    更新日期：1980-06-01 00:00:00