G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges.

Abstract:

:In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies, but many have failed either in phase I or II and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development.

journal_name

J Med Chem

authors

Ritter K,Buning C,Halland N,Pöverlein C,Schwink L

doi

10.1021/acs.jmedchem.5b01198

subject

Has Abstract

pub_date

2016-04-28 00:00:00

pages

3579-92

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章,评审
  • Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility.

    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

    authors: Nishizawa N,Takatsu Y,Kumano S,Kiba A,Ban J,Tsutsumi S,Matsui H,Matsumoto SI,Yamaguchi M,Ikeda Y,Kusaka M,Ohtaki T,Itoh F,Asami T

    更新日期:2016-10-13 00:00:00

  • Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors.

    abstract::Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhib...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.8b01133

    authors: Richardson BG,Jain AD,Potteti HR,Lazzara PR,David BP,Tamatam CR,Choma E,Skowron K,Dye K,Siddiqui Z,Wang YT,Krunic A,Reddy SP,Moore TW

    更新日期:2018-09-13 00:00:00

  • Synthesis and antitumor activity of 4- and 5-substituted derivatives of isoquinoline-1-carboxaldehyde thiosemicarbazone.

    abstract::Various substituted isoquinoline-1-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia. Condensation of 4-bromo-1-methylisoquinoline (4) with ammonium hydroxide, methylamine, ethylamine, and N-acetylethylenediamine gave the...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00021a012

    authors: Liu MC,Lin TS,Penketh P,Sartorelli AC

    更新日期:1995-10-13 00:00:00

  • Inhibition of chicken liver dihydrofolate reductase by 5-(substituted benzyl)-2,4-diaminopyrimidines. A quantitative structure-activity relationship and graphics analysis.

    abstract::The inhibition of chicken liver dihydrofolate reductase by a series of substituted benzylpyrimidines has been investigated. From the inhibition constants a quantitative structure-activity relationship has been formulated. This mathematical model is compared with molecular graphics models constructed from the X-ray cry...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00155a006

    authors: Selassie CD,Fang ZX,Li RL,Hansch C,Klein T,Langridge R,Kaufman BT

    更新日期:1986-05-01 00:00:00

  • Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2.

    abstract::It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11β-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-i...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.8b00328

    authors: Sakakibara R,Sasaki W,Onda Y,Yamaguchi M,Ushirogochi H,Hiraga Y,Sato K,Nishio M,Egi Y,Takedomi K,Shimizu H,Ohbora T,Akahoshi F

    更新日期:2018-07-12 00:00:00

  • Exploiting the therapeutic potential of 8-β-d-glucopyranosylgenistein: synthesis, antidiabetic activity, and molecular interaction with islet amyloid polypeptide and amyloid β-peptide (1-42).

    abstract::8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm501069h

    authors: Jesus AR,Dias C,Matos AM,de Almeida RF,Viana AS,Marcelo F,Ribeiro RT,Macedo MP,Airoldi C,Nicotra F,Martins A,Cabrita EJ,Jiménez-Barbero J,Rauter AP

    更新日期:2014-11-26 00:00:00

  • CCK peptides with combined features of hexa- and tetrapeptide CCK-A agonists.

    abstract::Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm990252e

    authors: Pierson ME,Comstock JM,Simmons RD,Julien R,Kaiser F,Rosamond JD

    更新日期:2000-06-15 00:00:00

  • Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols.

    abstract::Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibi...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00030a012

    authors: Pearce BC,Parker RA,Deason ME,Dischino DD,Gillespie E,Qureshi AA,Volk K,Wright JJ

    更新日期:1994-02-18 00:00:00

  • Synthesis and antimalarial activity of 2-guanidino-4-oxoimidazoline derivatives.

    abstract::A series of 2-guanidino-4-oxoimidazoline (deoxo-IZ) derivatives was prepared and showed potent antimalarial activities in rodent and Rhesus models. Compound 8e, the most potent analogues of this series, is the first non-8-aminoqinoline antimalarial that demonstrated radical curative activity in non-human primate by or...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm200111g

    authors: Liu X,Wang X,Li Q,Kozar MP,Melendez V,O'Neil MT,Lin AJ

    更新日期:2011-07-14 00:00:00

  • Discovery of imidazo[1,2-b][1,2,4]triazines as GABA(A) alpha2/3 subtype selective agonists for the treatment of anxiety.

    abstract::The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm051200u

    authors: Russell MG,Carling RW,Street LJ,Hallett DJ,Goodacre S,Mezzogori E,Reader M,Cook SM,Bromidge FA,Newman R,Smith AJ,Wafford KA,Marshall GR,Reynolds DS,Dias R,Ferris P,Stanley J,Lincoln R,Tye SJ,Sheppard WF,Sohal B,

    更新日期:2006-02-23 00:00:00

  • The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic.

    abstract::Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a defin...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/acs.jmedchem.8b00843

    authors: Namasivayam V,Vanangamudi M,Kramer VG,Kurup S,Zhan P,Liu X,Kongsted J,Byrareddy SN

    更新日期:2019-05-23 00:00:00

  • New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties.

    abstract::A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved t...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm031109v

    authors: Visentin S,Rolando B,Di Stilo A,Fruttero R,Novara M,Carbone E,Roussel C,Vanthuyne N,Gasco A

    更新日期:2004-05-06 00:00:00

  • Efficient preparations of the beta-glucuronides of dihydroartemisinin and structural confirmation of the human glucuronide metabolite.

    abstract::New and greatly improved preparations of the 12alpha,1'beta- (5) and 12beta,1'beta- (6) glucuronides of dihydroartemisinin (DHA, 2) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12alpha-epimer 5...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm001061a

    authors: O'Neill PM,Scheinmann F,Stachulski AV,Maggs JL,Park BK

    更新日期:2001-04-26 00:00:00

  • Ligand binding analysis for human alpha5beta1 integrin: strategies for designing new alpha5beta1 integrin antagonists.

    abstract::We report a three-dimensional model of the alpha5beta1 integrin headgroup bound to the most potent and selective ligand (SJ749) known to date. The model was built using the comparative protein modeling method, and it is consistent with experimental data. From this study, we identified two potentially important regions...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm040224i

    authors: Marinelli L,Meyer A,Heckmann D,Lavecchia A,Novellino E,Kessler H

    更新日期:2005-06-30 00:00:00

  • Design and synthesis of orally bioavailable aminopyrrolidinone histone deacetylase 6 inhibitors.

    abstract::Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective inhibitors as chemical biology tools and ultimately as new therapeutic a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm502011f

    authors: Lin X,Chen W,Qiu Z,Guo L,Zhu W,Li W,Wang Z,Zhang W,Zhang Z,Rong Y,Zhang M,Yu L,Zhong S,Zhao R,Wu X,Wong JC,Tang G

    更新日期:2015-03-26 00:00:00

  • Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

    abstract::Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered cli...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.1021/acs.jmedchem.5b00326

    authors: Röhrig UF,Majjigapu SR,Vogel P,Zoete V,Michielin O

    更新日期:2015-12-24 00:00:00

  • Syntheses and structure--activity relationships of novel apio and thioapio dideoxydidehydronucleosides as anti-HCMV agents.

    abstract::On the basis of the fact that apio dideoxynucleosides, in which the furanose oxygen and the C2 of the 2,3-dideoxyribose are transposed, exhibited potent anti-HIV activity and 2',3'-dideoxy-2',3'-didehydronucleosides also showed potent anti-HIV activity, we synthesized apio dideoxydidehydronucleosides in which the oxyg...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm000342f

    authors: Jeong LS,Kim HO,Moon HR,Hong JH,Yoo SJ,Choi WJ,Chun MW,Lee CK

    更新日期:2001-03-01 00:00:00

  • Design, synthesis, and biological activity of a family of novel ceramide analogues in chemoresistant breast cancer cells.

    abstract::Resistance to chemotherapy and endocrine therapy is a major cause of breast cancer treatment failure. We have synthesized six novel analogues using C8-ceramide as the lead analogue and studied their effect on hormone therapy resistant (MDA-MB-231) and chemoresistant (MCF-7TN-R) breast cancer cells. Pharmacologic inter...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm9009668

    authors: Antoon JW,Liu J,Gestaut MM,Burow ME,Beckman BS,Foroozesh M

    更新日期:2009-09-24 00:00:00

  • Prolyl oligopeptidase inhibition by N-acyl-pro-pyrrolidine-type molecules.

    abstract::Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm800944x

    authors: Kánai K,Arányi P,Böcskei Z,Ferenczy G,Harmat V,Simon K,Bátori S,Náray-Szabo G,Hermecz I

    更新日期:2008-12-11 00:00:00

  • Synthesis and evaluation of nitroheterocyclic carbamate prodrugs for use with nitroreductase-mediated gene-directed enzyme prodrug therapy.

    abstract::A variety of nitroheterocyclic carbamate prodrugs of phenylenediamine mustard and 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indoline (amino-seco-CBI-TMI), covering a wide range of reduction potential, were prepared and evaluated for use in gene-directed enzyme prodrug ther...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm030308b

    authors: Hay MP,Anderson RF,Ferry DM,Wilson WR,Denny WA

    更新日期:2003-12-04 00:00:00

  • Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase.

    abstract::A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm800914n

    authors: Barrow JC,Stauffer SR,Rittle KE,Ngo PL,Yang Z,Selnick HG,Graham SL,Munshi S,McGaughey GB,Holloway MK,Simon AJ,Price EA,Sankaranarayanan S,Colussi D,Tugusheva K,Lai MT,Espeseth AS,Xu M,Huang Q,Wolfe A,Pietrak B,Z

    更新日期:2008-10-23 00:00:00

  • Synthesis, NMDA receptor antagonist activity, and anticonvulsant action of 1-aminocyclobutanecarboxylic acid derivatives.

    abstract::A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones wa...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00051a005

    authors: Gaoni Y,Chapman AG,Parvez N,Pook PC,Jane DE,Watkins JC

    更新日期:1994-12-09 00:00:00

  • Nucleoside conjugates. 6. Synthesis and comparison of antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of corticosteroids and selected lipophilic alcohols.

    abstract::Five new P1-(steroid-21-yl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyro phosphates (ara-CDP-steroids), five 1-beta-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P1-(alkyl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyrophosphat e (ara-CDP-alkyl esters) have been prepared and eva...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00380a004

    authors: Hong CI,Kirisits AJ,Nechaev A,Buchheit DJ,West CR

    更新日期:1985-02-01 00:00:00

  • Investigations into the origin of the molecular recognition of several adenosine deaminase inhibitors.

    abstract::Inhibitors of adenosine deaminase (ADA, EC 3.5.4.4) are potential therapeutic agents for the treatment of various health disorders. Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities. We performed a SAR study involving a series of C2 or C8 substituted purine-riboside ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm101286g

    authors: Gillerman I,Fischer B

    更新日期:2011-01-13 00:00:00

  • Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design.

    abstract::A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 re...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm960092w

    authors: Melnick M,Reich SH,Lewis KK,Mitchell LJ Jr,Nguyen D,Trippe AJ,Dawson H,Davies JF 2nd,Appelt K,Wu BW,Musick L,Gehlhaar DK,Webber S,Shetty B,Kosa M,Kahil D,Andrada D

    更新日期:1996-07-05 00:00:00

  • New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives.

    abstract::A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00100a007

    authors: Bradbury RH,Allott CP,Dennis M,Fisher E,Major JS,Masek BB,Oldham AA,Pearce RJ,Rankine N,Revill JM

    更新日期:1992-10-30 00:00:00

  • Synthesis and antimalarial activity of artemisinin derivatives containing an amino group.

    abstract::In search of water-soluble artemisinin derivatives that are more stable than sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5) were synthesized and tested in mice. All products tested (except 5a and 5b) are the beta isomers. These basic compounds combined with organic acids (oxalic acid,...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm990552w

    authors: Li Y,Zhu YM,Jiang HJ,Pan JP,Wu GS,Wu JM,Shi YL,Yang JD,Wu BA

    更新日期:2000-04-20 00:00:00

  • Synthesis and biological evaluation of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b)pyridazines related to formycin prepared via ring closure of pyridazine precursors.

    abstract::All three amino-substituted 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazines (5, 19, and 20) structurally related to formycin A were prepared and tested for their antitumor and antiviral activity in cell culture. Dehydrative coupling of 4-amino-5-chloro-3-hydrazinopyridazine (7) with 3,4,6-tri-O-benzoyl-2,5-anh...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm00127a024

    authors: Kang Y,Larson SB,Robins RK,Revankar GR

    更新日期:1989-07-01 00:00:00

  • Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors.

    abstract::Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn(II) or Cu(II) in complex with 2,2'-bipyridine or 1,10-phenanthroline with similar potencies (EC(50) from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3. These actions were depende...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm301121j

    authors: Thiele S,Malmgaard-Clausen M,Engel-Andreasen J,Steen A,Rummel PC,Nielsen MC,Gloriam DE,Frimurer TM,Ulven T,Rosenkilde MM

    更新日期:2012-09-27 00:00:00

  • Discovery and structure-activity relationship of 3-aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis inducers and potential anticancer agents.

    abstract::We have identified 5-(3-chlorothiophen-2-yl)-3-(4-trifluoromethylphenyl)-1,2,4-oxadiazole (1d) as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening assay. Compound 1d has good activity against several breast and colorectal cancer cell lines but is inactive against several other ca...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章

    doi:10.1021/jm050292k

    authors: Zhang HZ,Kasibhatla S,Kuemmerle J,Kemnitzer W,Ollis-Mason K,Qiu L,Crogan-Grundy C,Tseng B,Drewe J,Cai SX

    更新日期:2005-08-11 00:00:00