Discovery of bicycloalkyl urea melanin concentrating hormone receptor antagonists: orally efficacious antiobesity therapeutics.

abstract：:We here report the synthesis of compounds structurally related to the high-affinity dopamine D(3) receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (1). All compounds were specifically designed as potential PET radioligands for brain D(3) receptors visualization, havin...

journal_title：Journal of medicinal chemistry

authors： Leopoldo M,Lacivita E,De Giorgio P,Colabufo NA,Niso M,Berardi F,Perrone R

更新日期：2006-01-12 00:00:00

abstract：:Three analogs of luteinizing hormone-releasing hormone (LH-RH) of the structure less than Glu-His-Trp-Ser-Tyr-Gly-Gly-Leu-Arg-Pro-Gly-NH2, involving substitutions inpositions 1, 3, and 8 with nonprotein amino acids, have been synthesized by the solid-phase method. They are [pyro-L-alpha-(1-aminoadipic)]-LH-RH, [3-(2-n...

journal_title：Journal of medicinal chemistry

authors： Prasad KU,Roeske RW,Weitl FL,Vilchez-Martinez JA,Schally AV

更新日期：1976-04-01 00:00:00

abstract：:N delta-Acyl derivatives of the potent folylpolyglutamate synthetase (FPGS) inhibitor N alpha-(4-amino-4-deoxypteroyl)-L-ornithine (APA-L-Orn) were synthesized from N alpha-(4-amino-4-deoxy-N10-formylpteroyl)-L-ornithine by reaction with an N-(acyloxy)succinimide or acyl anhydride, followed by deformylation with base....

journal_title：Journal of medicinal chemistry

authors： Rosowsky A,Bader H,Cucchi CA,Moran RG,Kohler W,Freisheim JH

更新日期：1988-07-01 00:00:00

abstract：:Notch is a membrane inserted protein activated by the membrane-inserted γ-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we h...

journal_title：Journal of medicinal chemistry

authors： Juillerat-Jeanneret L,Flohr A,Schneider M,Walter I,Wyss JC,Kumar R,Golshayan D,Aebi JD

更新日期：2015-10-22 00:00:00

abstract：:SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to ...

journal_title：Journal of medicinal chemistry

authors： Geronikaki A,Eleftheriou P,Vicini P,Alam I,Dixit A,Saxena AK

更新日期：2008-09-11 00:00:00

abstract：:A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library wa...

journal_title：Journal of medicinal chemistry

authors： Goto Y,Arai-Otsuki S,Tachibana Y,Ichikawa D,Ozaki S,Takahashi H,Iwasawa Y,Okamoto O,Okuda S,Ohta H,Sagara T

更新日期：2006-02-09 00:00:00

abstract：:The antimicrobial and cytotoxic properties of a series of 9,10-dihydrophenanthrenes structurally related to juncusol (1a), a postulated phytoalexin with confirmed cytotoxic properties, are detailed. Two simple 9,10-dihydrophenanthrenes, 2,7-dihydroxy-3,8-dimethyl-9,10-dihydrophenanthrene (2h, desvinyljuncusol) and 2-h...

journal_title：Journal of medicinal chemistry

authors： Boger DL,Mitscher LA,Mullican MD,Drake SD,Kitos P

更新日期：1985-10-01 00:00:00

abstract：:In this article, we report the findings of a comprehensive structure-activity relationship study of N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters, in which novel analogues were designed, synthesized, and evaluated in vitro for antiproliferative effect. Two new compounds, 2 and 16, showed potent nanomolar activit...

journal_title：Journal of medicinal chemistry

authors： Mooney A,Tiedt R,Maghoub T,O'Donovan N,Crown J,White B,Kenny PT

更新日期：2012-06-14 00:00:00

abstract：:Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds cov...

journal_title：Journal of medicinal chemistry

authors： Carmi C,Cavazzoni A,Vezzosi S,Bordi F,Vacondio F,Silva C,Rivara S,Lodola A,Alfieri RR,La Monica S,Galetti M,Ardizzoni A,Petronini PG,Mor M

更新日期：2010-03-11 00:00:00

abstract：:Synthetic routes were developed to access a variety of novel 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-one analogs which were evaluated as 5-lipoxygenase (5-LO) inhibitors. The parent structure, 1-phenylperhydro-1,2,4-triazin-3-one (4), was found to be a selective inhibitor of 5-LO in broken cell, intact cell, and human...

journal_title：Journal of medicinal chemistry

authors： Bhatia PA,Brooks CD,Basha A,Ratajczyk JD,Gunn BP,Bouska JB,Lanni C,Young PR,Bell RL,Carter GW

更新日期：1996-09-27 00:00:00

abstract：:Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensi...

journal_title：Journal of medicinal chemistry

authors： Ellingboe JW,Collini MD,Quagliato D,Chen J,Antane M,Schmid J,Hartupee D,White V,Park CH,Tanikella T,Bagli JF

更新日期：1998-10-22 00:00:00

abstract：:On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an...

journal_title：Journal of medicinal chemistry

authors： Surleraux DL,de Kock HA,Verschueren WG,Pille GM,Maes LJ,Peeters A,Vendeville S,De Meyer S,Azijn H,Pauwels R,de Bethune MP,King NM,Prabu-Jeyabalan M,Schiffer CA,Wigerinck PB

更新日期：2005-03-24 00:00:00

abstract：:A series of 2,3-dihydrobenzofuran-5-acetic acids and related compounds was prepared as potential antiinflammatory agents. As measured by the carrageenan-induced edema method for the preliminary screening test, introduction of a methyl group alpha to the acetic acid function enhanced the antiinflammatory activity, and ...

journal_title：Journal of medicinal chemistry

authors： Hirose N,Kuriyama S,Kato Y,Toyoshima S

更新日期：1976-02-01 00:00:00

abstract：:New beta-adrenergic blocking agents, most of which do not contain an aromatic nucleus, were synthesized. They were derived either from alkylamino-aliphatic oxime ethers or alkylamino-aliphatic ethers. Most active among these are O-[3-(tert-butylamino)-2-hydroxypropyl]acetoxime (8; trachea pA2 = 7.65) and 1-isobutoxy-3...

journal_title：Journal of medicinal chemistry

authors： Leclerc G,Bieth N,Schwartz J

更新日期：1980-06-01 00:00:00

abstract：:Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising mol...

journal_title：Journal of medicinal chemistry

authors： Le TG,Kundu A,Ghoshal A,Nguyen NH,Preston S,Jiao Y,Ruan B,Xue L,Huang F,Keiser J,Hofmann A,Chang BCH,Garcia-Bustos J,Wells TNC,Palmer MJ,Jabbar A,Gasser RB,Baell JB

更新日期：2019-01-24 00:00:00

abstract：:Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGF...

journal_title：Journal of medicinal chemistry

authors： Planken S,Behenna DC,Nair SK,Johnson TO,Nagata A,Almaden C,Bailey S,Ballard TE,Bernier L,Cheng H,Cho-Schultz S,Dalvie D,Deal JG,Dinh DM,Edwards MP,Ferre RA,Gajiwala KS,Hemkens M,Kania RS,Kath JC,Matthews J,Murra

更新日期：2017-04-13 00:00:00

abstract：:Fluorescence spectrometry data by Tyulmenkov and Klinge (Arch. Biochem. Biophys. 2000, 381, 135-142) suggest the presence of a second binding site in both subtypes ER alpha and ER beta of the estrogen receptor (ER). A cavity previously described as a solvent channel was located in close proximity to the steroid bindin...

journal_title：Journal of medicinal chemistry

authors： van Hoorn WP

更新日期：2002-01-31 00:00:00

abstract：:A series of 3-hydroxy-substituted analogues (3-7) of the mu selective opioid antagonist cyprodime has been synthesized in order to evaluate the role of a hydroxy group at C-3 concerning mu opioid antagonist selectivity. Compounds 3-7 were tested in bioassays (electrical stimulated mouse vas deferens preparation and my...

journal_title：Journal of medicinal chemistry

authors： Schmidhammer H,Jennewein HK,Krassnig R,Traynor JR,Patel D,Bell K,Froschauer G,Mattersberger K,Jachs-Ewinger C,Jura P

更新日期：1995-08-04 00:00:00

abstract：:The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid N-benzo[1,3]dioxol-5-ylmethyl)amide (JTE-907; 9b), served as the lead compound for investigating the structure-activity relationships of its analogues and in the search for more potent and ...

journal_title：Journal of medicinal chemistry

authors： Raitio KH,Savinainen JR,Vepsäläinen J,Laitinen JT,Poso A,Järvinen T,Nevalainen T

更新日期：2006-03-23 00:00:00

abstract：:A series of pyridines and other six-membered ring heterocycles connected to a biphenyltetrazole with a -CH2-NR'-link (1) were discovered to be potent angiotensin II antagonists. In the pyrimidine carboxylic acid series (W = CR, X = N, Y = CH, Z = COOH), compounds with an alkyl group (R') on the exocyclic nitrogen were...

journal_title：Journal of medicinal chemistry

authors： Winn M,De B,Zydowsky TM,Altenbach RJ,Basha FZ,Boyd SA,Brune ME,Buckner SA,Crowell D,Drizin I

更新日期：1993-09-03 00:00:00

abstract：:Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically, many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GA...

journal_title：Journal of medicinal chemistry

authors： Fritch PC,McNaughton-Smith G,Amato GS,Burns JF,Eargle CW,Roeloffs R,Harrison W,Jones L,Wickenden AD

更新日期：2010-01-28 00:00:00

abstract：:Details of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors (NNRTIs) have been elucidated using a biosensor-based approach. This initial study was performed with HIV-1 reverse transcriptase mutant K103N, the phenethylthioazolylthiourea compound (PETT) MIV-150, and the three NNRTIs lice...

journal_title：Journal of medicinal chemistry

authors： Geitmann M,Unge T,Danielson UH

更新日期：2006-04-20 00:00:00

abstract：:Various sulfonyl-containing compounds (e.g. sulfonamides, sulfones) bind at human 5-HT6 serotonin receptors, but it has been difficult relating the binding mode(s) of such agents to one another, even though many possess a common SO2 moiety, to identify a common pharmacophore model(s). On the basis of the hypothesis th...

journal_title：Journal of medicinal chemistry

authors： Sikazwe D,Bondarev ML,Dukat M,Rangisetty JB,Roth BL,Glennon RA

更新日期：2006-08-24 00:00:00

abstract：:7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). 3-(3,5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-tert-butylureas by alkylation with benzyl o...

journal_title：Journal of medicinal chemistry

authors： Thompson AM,Delaney AM,Hamby JM,Schroeder MC,Spoon TA,Crean SM,Showalter HD,Denny WA

更新日期：2005-07-14 00:00:00

abstract：:A series of novel 1'-methylxanthene-9-spiro-4'-piperidines has been prepared in the search for opiate analgesics with improved pharmacological properties. It has been found that introduction of a hydroxyl group into the 4-position of the xanthenespiropiperidine nucleus produces a potent mu-opiate agonist. The structur...

journal_title：Journal of medicinal chemistry

authors： Galt RH,Horbury J,Matusiak ZS,Pearce RJ,Shaw JS

更新日期：1989-10-01 00:00:00

abstract：:Starting from the high-throughput screening hit 1a, novel cathepsin K inhibitors have been developed based on a purine scaffold. High-resolution X-ray structures of several derivatives have revealed the binding mode of these unique cysteine protease inhibitors. ...

journal_title：Journal of medicinal chemistry

authors： Altmann E,Cowan-Jacob SW,Missbach M

更新日期：2004-11-18 00:00:00

abstract：:9,11-Secoestradiol (9) and 11-hydroxy-9,11-secoestradiol (12) have been synthesized starting from 17-acetoxyestradiol 3-methyl ether (1) and found to possess significant antifertility activity in rats. 3-Methoxy-9,11-seco-9-oxo-17beta-acetoxyestra-1,3,5(10)-trien-11-oic acid (2), prepared by CrO3 oxidation of 1, on h...

journal_title：Journal of medicinal chemistry

authors： Kole P,Ray S,Kamboj VP,Anand N

更新日期：1975-07-01 00:00:00

abstract：:The sponge-derived polyketide macrolides fijianolides A (1) and B (2), isolaulimalide and laulimalide, have taxol-like microtubule-stabilizing activity, and the latter exhibits potent cytotoxicity. Insight on the biogeographical and phenotypic variations of Cacospongia mycofijiensis is presented that will enable a fut...

journal_title：Journal of medicinal chemistry

authors： Johnson TA,Tenney K,Cichewicz RH,Morinaka BI,White KN,Amagata T,Subramanian B,Media J,Mooberry SL,Valeriote FA,Crews P

更新日期：2007-08-09 00:00:00

abstract：:A number of analogues of ibotenic acid [(RS)-3-hydroxy-5- isoxazoleglycine ] were synthesized; they were tested as excitants on neurons in the cat spinal cord, by using microelectrophoretic techniques, and as inhibitors of the binding of kainic acid (KA) in vitro, by using synaptic membranes prepared from rat brains. ...

journal_title：Journal of medicinal chemistry

authors： Krogsgaard-Larsen P,Nielsen EO,Curtis DR

更新日期：1984-05-01 00:00:00

abstract：:Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope ...

journal_title：Journal of medicinal chemistry

authors： Waghray D,Zhang Q

更新日期：2018-06-28 00:00:00