当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > The development of cyclic sulfolanes as novel and high-affinity P2 ligands for HIV-1 protease inhibitors.

The development of cyclic sulfolanes as novel and high-affinity P2 ligands for HIV-1 protease inhibitors.

Abstract：

:Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2-isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (IC50 3.5 nM, CIC95 50 +/- 14 nM) of comparable in vitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the P1' decahydroisoquinoline derivative.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Ghosh AK,Lee HY,Thompson WJ,Culberson C,Holloway MK,McKee SP,Munson PM,Duong TT,Smith AM,Darke PL

doi

10.1021/jm00034a016

subject

Has Abstract,Author List Incomplete

pub_date

1994-04-15 00:00:00

pages

1177-88

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

37

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Benzophenone derivatives: a novel series of potent and selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase.

    abstract：:A series of benzophenone derivatives has been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (RT) and the growth of HIV-1 in MT-4 cells. Through the use of the structure-activity relationships within this series of compounds and computational chemistry techniques, a binding conformation is prop...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00010a010

    authors： Wyatt PG,Bethell RC,Cammack N,Charon D,Dodic N,Dumaitre B,Evans DN,Green DV,Hopewell PL,Humber DC

    更新日期：1995-05-12 00:00:00

  • beta-Adrenergic blocking agents. 17. 1-Phenoxy-3-phenoxyalkylamino-2-propanols and 1-alkoxyalkylamino-3-phenoxy-2-propanols.

    abstract：:The synthesis is described of a series of derivatives of 1-phenoxy-3-phenoxyalkylamino-2-propanols and 1-alkoxyalkylamino-3-phenoxy-2-propranols. The compounds were investigated for their beta-adrenoceptor blocking properties and many showed a surprising degree of cardioselectivity when tested in vivo in anesthetized ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00222a022

    authors： Smith LH,Tucker H

    更新日期：1977-12-01 00:00:00

  • Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors.

    abstract：:A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration proces...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm8003784

    authors： Pasquini S,Mugnaini C,Tintori C,Botta M,Trejos A,Arvela RK,Larhed M,Witvrouw M,Michiels M,Christ F,Debyser Z,Corelli F

    更新日期：2008-08-28 00:00:00

  • Feature selection for structure-activity correlation using binary particle swarms.

    abstract：:We present a new feature selection algorithm for structure-activity and structure-property correlation based on particle swarms. Particle swarms explore the search space through a population of individuals that adapt by returning stochastically toward previously successful regions, influenced by the success of their n...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0104668

    authors： Agrafiotis DK,Cedeño W

    更新日期：2002-02-28 00:00:00

  • DL-threo-beta-Fluoroaspartate and DL-threo-beta-fluoroasparagine: selective cytotoxic agents for mammalian cells in culture.

    abstract：:Absolute configuration assignments have been made for the diastereomers of DL-beta-fluoroaspartate by X-ray analysis. The cytotoxicity of these isomers against various mammalian cells was examined. DL-threo-beta-Fluoroaspartate shows selective cytotoxicity. Growth of the most sensitive cells is completely inhibited by...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00347a013

    authors： Stern AM,Foxman BM,Tashjian AH Jr,Abeles RH

    更新日期：1982-05-01 00:00:00

  • Quick assembly of 1,4-diphenyltriazoles as probes targeting beta-amyloid aggregates in Alzheimer's disease.

    abstract：:Accumulation of beta-amyloid aggregates (Abeta) in the brain is linked to the pathogenesis of Alzheimer's disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Abeta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm070467l

    authors： Qu W,Kung MP,Hou C,Oya S,Kung HF

    更新日期：2007-07-12 00:00:00

  • 4-N-, 4-S-, and 4-O-chloroquine analogues: influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria.

    abstract：:Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm701478a

    authors： Natarajan JK,Alumasa JN,Yearick K,Ekoue-Kovi KA,Casabianca LB,de Dios AC,Wolf C,Roepe PD

    更新日期：2008-06-26 00:00:00

  • Mapping the turkey erythrocyte beta receptor: a distance geometry approach.

    abstract：:Extensions and refinements of the receptor mapping method as originally developed by Crippen are presented. In a set of newly developed algorithms measures are taken to reduce the number of required energy parameters to a statistically acceptable degree. The most important measure is the incorporation of lipophilicity...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00152a017

    authors： Linschoten MR,Bultsma T,IJzerman AP,Timmerman H

    更新日期：1986-02-01 00:00:00

  • Derivatives of 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine as central nervous system agents.

    abstract：:Four 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepines were prepared and evaluated as central nervous system agents. All were active psychotropic agents as determined by animal screening tests. The most interesting compound, 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, showed dual activity as an ant...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00178a020

    authors： Wright WB Jr,Greenblatt EN,Day IP,Quinones NQ,Hardy RA Jr

    更新日期：1980-04-01 00:00:00

  • Abasic site recognition in DNA as a new strategy to potentiate the action of anticancer alkylating drugs?

    abstract：:Inhibition of abasic site repair in the cell seems an attractive strategy to potentiate the action of antitumor DNA alkylating drugs. Molecules that bind specifically and strongly to the abasic site are possible candidates to achieve such inhibition. We explored this strategy by preparing molecule 4 that incorporates ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9901428

    authors： Belmont P,Jourdan M,Demeunynck M,Constant JF,Garcia J,Lhomme J,Carez D,Croisy A

    更新日期：1999-12-16 00:00:00

  • Synthesis of 2-(p-chlorobenzyl)-3-aryl-6-methoxybenzofurans as selective ligands for antiestrogen-binding sites. Effects on cell proliferation and cholesterol synthesis.

    abstract：:A series of nonsteroidal compounds, 2-(p-chlorobenzyl)-3-aryl-6- methoxybenzofurans derived from the 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones has been synthesized. The key steps in the synthesis were reactions of 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones with the arylorganometallic reagents followed b...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00086a002

    authors： Teo CC,Kon OL,Sim KY,Ng SC

    更新日期：1992-04-17 00:00:00

  • Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design.

    abstract：:Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetam...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00783

    authors： Narjes F,Xue Y,von Berg S,Malmberg J,Llinas A,Olsson RI,Jirholt J,Grindebacke H,Leffler A,Hossain N,Lepistö M,Thunberg L,Leek H,Aagaard A,McPheat J,Hansson EL,Bäck E,Tångefjord S,Chen R,Xiong Y,Hongbin G,Hansson

    更新日期：2018-09-13 00:00:00

  • Synthesis and antitumor activity of tropolone derivatives. 5.

    abstract：:As part of a study on the structure-activity relationship of antitumor-active tropolone derivatives, a series of bistropone analogues, related to potently active bistropolone 1a, were synthesized and tested for their antitumor activity in in vitro (KB cell) and in vivo (leukemia P388 in mice) systems. The methoxytropo...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00390a022

    authors： Yamato M,Hashigaki K,Sakai J,Takeuchi Y,Tsukagoshi S,Tashiro T,Tsuruo T

    更新日期：1987-07-01 00:00:00

  • Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and homology modeling.

    abstract：:Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inh...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060380k

    authors： Gunby RH,Ahmed S,Sottocornola R,Gasser M,Redaelli S,Mologni L,Tartari CJ,Belloni V,Gambacorti-Passerini C,Scapozza L

    更新日期：2006-09-21 00:00:00

  • Studies on 1,2,3-triazoles. 10. Synthesis and antiallergic properties of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazoles and their S-oxides.

    abstract：:Selected derivatives of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole, a new heterocyclic ring system, and their S-oxides have been prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. Several of the compounds show intravenous potencies similar to or greater than that o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00368a021

    authors： Buckle DR,Rockell CJ,Smith H,Spicer BA

    更新日期：1984-02-01 00:00:00

  • Syntheses of 2-nitroimidazole derivatives conjugated with 1,4,7-triazacyclononane-N,N'-diacetic acid labeled with F-18 using an aluminum complex method for hypoxia imaging.

    abstract：:Hypoxia imaging is important for diagnosis of ischemic diseases, and thus various (18)F-labeled radiopharmaceuticals have been developed. However, (18)F-labeling requires multistep procedures including azeotropic distillation, which is complicated and difficult to automate. Recently, (18)F-labeling method using Al-F c...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm201611a

    authors： Hoigebazar L,Jeong JM,Lee JY,Shetty D,Yang BY,Lee YS,Lee DS,Chung JK,Lee MC

    更新日期：2012-04-12 00:00:00

  • New dibenzothiadiazepine derivatives with antidepressant activities.

    abstract：:A new series of 11-[(aminoalkyl)carbonyl] derivatives of 6,11-dihydrodibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (10-39) were synthesized and evaluated for potential antidepressant activity in the apomorphine-induced hypothermia (Apo 16) test. Effects on reserpine-induced hypothermia and toxicity for the most potent ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00108a018

    authors： Giannotti D,Viti G,Sbraci P,Pestellini V,Volterra G,Borsini F,Lecci A,Meli A,Dapporto P,Paoli P

    更新日期：1991-04-01 00:00:00

  • Biologically active oligodeoxyribonucleotides. 5. 5'-End-substituted d(TGGGAG) possesses anti-human immunodeficiency virus type 1 activity by forming a G-quadruplex structure.

    abstract：:A series of hexadeoxyribonucleotides (6-mers), d(TGGGAG), substituted with a variety of aromatic groups at the 5'-end were synthesized and tested for anti-human immunodeficiency virus type 1 (HIV-1) activity. While unmodified d(TGGGAG) (31) had no anti-HIV-1 activity, compound 23 with a 3,4-di(benzyloxy)benzyl (DBB) g...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm970658w

    authors： Hotoda H,Koizumi M,Koga R,Kaneko M,Momota K,Ohmine T,Furukawa H,Agatsuma T,Nishigaki T,Sone J,Tsutsumi S,Kosaka T,Abe K,Kimura S,Shimada K

    更新日期：1998-09-10 00:00:00

  • Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics.

    abstract：:A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00254

    authors： Qin L,Ren L,Wan S,Liu G,Luo X,Liu Z,Li F,Yu Y,Liu J,Wei Y

    更新日期：2017-05-11 00:00:00

  • Synthesis of new alkylaminooxysterols with potent cell differentiating activities: identification of leads for the treatment of cancer and neurodegenerative diseases.

    abstract：:We describe here the syntheses and the biological properties of new alkylaminooxysterols. Compounds were synthesized through the trans-diaxial aminolysis of 5,6-alpha-epoxysterols with various natural amines including histamine, putrescine, spermidine, or spermine. The regioselective synthesis of these 16 new 5alpha-h...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901063e

    authors： de Medina P,Paillasse MR,Payré B,Silvente-Poirot S,Poirot M

    更新日期：2009-12-10 00:00:00

  • A novel approach for the development of selective Cdk4 inhibitors: library design based on locations of Cdk4 specific amino acid residues.

    abstract：:Identification of a selective inhibitor for a particular protein kinase without inhibition of other kinases is critical for use as a biological tool or drug. However, this is very difficult because there are hundreds of homologous kinases and their kinase domains including the ATP binding pocket have a common folding ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm010326y

    authors： Honma T,Yoshizumi T,Hashimoto N,Hayashi K,Kawanishi N,Fukasawa K,Takaki T,Ikeura C,Ikuta M,Suzuki-Takahashi I,Hayama T,Nishimura S,Morishima H

    更新日期：2001-12-20 00:00:00

  • Iodine-containing organic carbonates as investigative radiopaque compounds.

    abstract：:Carbonates containing an iodinated aromatic ring on one side of the carbonate linkage and an alkyl group on the other were prepared. The aromatic side consisted of p-iodophenyl, p-iodobenzyl, m-iodobenzyl, 3,5-diiodobenzyl, m-amino-2,4,6-triiodobenzyl, m-acetamido-2,4,6-triiodobenzyl, p-iodophenethyl, p-iodo-sec-phene...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00234a002

    authors： Newton BN

    更新日期：1976-12-01 00:00:00

  • Low molecular weight, non-peptide fibrinogen receptor antagonists.

    abstract：:The tetrapeptide H-Arg-Gly-Asp-Ser-OH (1) (RGDS), representing a recognition sequence of fibrinogen for its platelet receptor GP IIb-IIIa (integrin alpha IIb beta 3), served as lead compound for the development of highly potent and selective fibrinogen receptor antagonists. Replacement of the N-terminal arginine by p-...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00101a017

    authors： Alig L,Edenhofer A,Hadváry P,Hürzeler M,Knopp D,Müller M,Steiner B,Trzeciak A,Weller T

    更新日期：1992-11-13 00:00:00

  • X-ray Structure Analysis of Indazolium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) Bound to Human Serum Albumin Reveals Two Ruthenium Binding Sites and Provides Insights into the Drug Binding Mechanism.

    abstract：:Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00600

    authors： Bijelic A,Theiner S,Keppler BK,Rompel A

    更新日期：2016-06-23 00:00:00

  • Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.

    abstract：:The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sit...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.0c01063

    authors： Hoffman RL,Kania RS,Brothers MA,Davies JF,Ferre RA,Gajiwala KS,He M,Hogan RJ,Kozminski K,Li LY,Lockner JW,Lou J,Marra MT,Mitchell LJ Jr,Murray BW,Nieman JA,Noell S,Planken SP,Rowe T,Ryan K,Smith GJ 3rd,Solowiej

    更新日期：2020-11-12 00:00:00

  • Synthesis and in vitro antiplatelet activity of new 4-(1-piperazinyl)coumarin derivatives. Human platelet phosphodiesterase 3 inhibitory properties of the two most effective compounds described and molecular modeling study on their interactions with phosp

    abstract：:The synthesis and in vitro antiplatelet activity significant data of coumarin derivatives 5i-x and quinolin-2(1H)-one derivatives 22a,b, as well as the corresponding structure-activity relationships are described. The recently reported 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin 5f and its potent 7-(2-morp...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0611511

    authors： Roma G,Di Braccio M,Grossi G,Piras D,Leoncini G,Bruzzese D,Signorello MG,Fossa P,Mosti L

    更新日期：2007-06-14 00:00:00

  • Characterization of Inhibition Reveals Distinctive Properties for Human and Saccharomyces cerevisiae CRM1.

    abstract：:The receptor CRM1 is responsible for the nuclear export of many tumor-suppressor proteins and viral ribonucleoproteins. This renders CRM1 an interesting target for therapeutic intervention in diverse cancer types and viral diseases. Structural studies of Saccharomyces cerevisiae CRM1 ( Sc ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.0c00143

    authors： Shaikhqasem A,Dickmanns A,Neumann P,Ficner R

    更新日期：2020-07-23 00:00:00

  • Drugs derived from cannabinoids. 2. Basic esters of nitrogen and carbocyclic analogs.

    abstract：:Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00226a002

    authors： Razdan RK,Terris BZ,Pars HG,Plotnikoff NP,Dodge PW,Dren AT,Kyncl J,Somani P

    更新日期：1976-04-01 00:00:00

  • Spiro[(dihydropyrazin-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)]-based cytotoxic agents: structure-activity relationship studies on the substituent at N4-position of the diketopiperazine domain.

    abstract：:Analogues of the previously reported potent cytotoxic spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] derivatives (3, 3') were prepared to explore new structural requirements at the diketopiperazine domain for the cytotoxic activity. The in vitro activity was evaluated against t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm7013056

    authors： Gomez-Monterrey I,Campiglia P,Carotenuto A,Stiuso P,Bertamino A,Sala M,Aquino C,Grieco P,Morello S,Pinto A,Ianelli P,Novellino E

    更新日期：2008-05-22 00:00:00

  • Syntheses and antifolate activity of 5-methyl-5-deaza analogues of aminopterin, methotrexate, folic acid, and N10-methylfolic acid.

    abstract：:Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepar...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00156a029

    authors： Piper JR,McCaleb GS,Montgomery JA,Kisliuk RL,Gaumont Y,Sirotnak FM

    更新日期：1986-06-01 00:00:00