Novel purine nitrile derived inhibitors of the cysteine protease cathepsin K.

abstract：:A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules t...

journal_title：Journal of medicinal chemistry

authors： Peese KM,Allard CW,Connolly T,Johnson BL,Li C,Patel M,Sorensen ME,Walker MA,Meanwell NA,McAuliffe B,Minassian B,Krystal M,Parker DD,Lewis HA,Kish K,Zhang P,Nolte RT,Simmermacher J,Jenkins S,Cianci C,Naidu BN

更新日期：2019-02-14 00:00:00

abstract：:New acetamidines structurally related to N-(3-(aminomethyl)benzyl)acetamidine (1, W1400) were designed as inhibitors of inducible nitric oxide synthase (iNOS). Six compounds were found to be selective for iNOS over endothelial nitric oxide synthase (eNOS), and among them, the most active and selective compound was the...

journal_title：Journal of medicinal chemistry

authors： Maccallini C,Patruno A,Besker N,Alì JI,Ammazzalorso A,De Filippis B,Franceschelli S,Giampietro L,Pesce M,Reale M,Tricca ML,Re N,Felaco M,Amoroso R

更新日期：2009-03-12 00:00:00

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

authors： Butler DE,Wise LD,DeWald HA

更新日期：1984-11-01 00:00:00

abstract：:7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661, 1) is a potent inhibitor of the enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). In contrast to other inhibitors of PNMT, it is also highly selective toward PNMT in comparison with its affinity toward the alpha 2-adrenoceptor (PNMT Ki = 0....

journal_title：Journal of medicinal chemistry

authors： Grunewald GL,Dahanukar VH,Caldwell TM,Criscione KR

更新日期：1997-12-05 00:00:00

abstract：:(E)-Vinylphosphonate ((E)-VP), a metabolically stable phosphate mimic at the 5'-end of the antisense strand, enhances the in vivo potency of siRNA. Here we describe a straightforward synthetic approach to incorporate a nucleotide carrying a vinylphosphonate (VP) moiety at the 5'-end of oligonucleotides under standard ...

journal_title：Journal of medicinal chemistry

authors： Parmar RG,Brown CR,Matsuda S,Willoughby JLS,Theile CS,Charissé K,Foster DJ,Zlatev I,Jadhav V,Maier MA,Egli M,Manoharan M,Rajeev KG

更新日期：2018-02-08 00:00:00

abstract：:(E)-5-(2-Bromovinyl)-2'-deoxy-5'-O-(3-methyl-2-oxo-5-formyl-1,3,2- oxazaphosphacyclopentan-2-yl)uridine has been synthesized and, under physiological conditions and without the necessity for enzyme activity, has been shown to yield the 5'-nucleotide in vitro. Unfortunately this compound is not sufficiently stable in s...

journal_title：Journal of medicinal chemistry

authors： Kumar A,Coe PL,Jones AS,Walker RT,Balzarini J,De Clercq E

更新日期：1990-09-01 00:00:00

abstract：:Continuing structure-activity studies on the anticonvulsant activity of analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective index (TD50/ED50) of > 4.5 are reported. An in-depth analysis of this moiety was studied employing the Topliss...

journal_title：Journal of medicinal chemistry

authors： Farrar VA,Ciechanowicz-Rutkowska M,Grochowski J,Serda P,Pilati T,Filippini G,Hinko CN,el-Assadi A,Moore JA,Edafiogho IO

更新日期：1993-11-12 00:00:00

abstract：:Due to their role in many important signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive targets for the development of experimental therapeutics for cancer, metabolic, and immunological disorders. Recent efforts to develop small molecule inhibitors for these lipid kinases resulted i...

journal_title：Journal of medicinal chemistry

authors： Manz TD,Sivakumaren SC,Ferguson FM,Zhang T,Yasgar A,Seo HS,Ficarro SB,Card JD,Shim H,Miduturu CV,Simeonov A,Shen M,Marto JA,Dhe-Paganon S,Hall MD,Cantley LC,Gray NS

更新日期：2020-05-14 00:00:00

abstract：:Despite a myriad of available pharmacotherapies for the treatment of type 2 diabetes (T2D), challenges still exist in achieving glycemic control. Several novel glucose-lowering strategies are currently under clinical investigation, highlighting the need for more robust treatments. Previously, we have shown that suppre...

journal_title：Journal of medicinal chemistry

authors： Lin H,Sharabi K,Lin L,Ruiz C,Zhu D,Cameron MD,Novick SJ,Griffin PR,Puigserver P,Kamenecka TM

更新日期：2021-01-28 00:00:00

abstract：:The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary ...

journal_title：Journal of medicinal chemistry

authors： Rowley M,Hallett DJ,Goodacre S,Moyes C,Crawforth J,Sparey TJ,Patel S,Marwood R,Patel S,Thomas S,Hitzel L,O'Connor D,Szeto N,Castro JL,Hutson PH,MacLeod AM

更新日期：2001-05-10 00:00:00

abstract：:A variety of 8-substituted guanosine and 2'-deoxyguanosine derivatives were synthesized and tested as inducers of the differentiation of Friend murine erythroleukemia cells in culture. The most active agents in the guanosine series were 8-substituted-N(CH3)2, -NHCH3, -NH2, -OH, and -SO2CH3, which caused 68, 42, 34, 33...

journal_title：Journal of medicinal chemistry

authors： Lin TS,Cheng JC,Ishiguro K,Sartorelli AC

更新日期：1985-09-01 00:00:00

abstract：:A variation of the bromine substitution from 6- to 7-position converts the glycogen synthase kinase-3alpha/beta-(GSK-3-alpha/beta) selective inhibitor 6-bromoindirubin-3'-oxime (6BIO) to a potent inhibitor of Aurora B and C kinases. The novel indirubin analogue 7-bromoindirubin-3'-oxime (7BIO) demonstrated unexpected ...

journal_title：Journal of medicinal chemistry

authors： Myrianthopoulos V,Magiatis P,Ferandin Y,Skaltsounis AL,Meijer L,Mikros E

更新日期：2007-08-23 00:00:00

abstract：:Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indica...

journal_title：Journal of medicinal chemistry

authors： Patel G,Karver CE,Behera R,Guyett PJ,Sullenberger C,Edwards P,Roncal NE,Mensa-Wilmot K,Pollastri MP

更新日期：2013-05-23 00:00:00

abstract：:A series of 3-methyl-3-(m-hydroxyphenyl)piperidines with N-substituent variations have been synthesized and resolved, and an X-ray crystal structure of one analogue was determined. The compounds have been characterized, pharmacologically, by detailed opiate receptor binding studies and determination of in vivo analges...

journal_title：Journal of medicinal chemistry

authors： Cheng A,Uyeno E,Polgar W,Toll L,Lawson JA,DeGraw JI,Loew G,Camerman A,Camerman N

更新日期：1986-04-01 00:00:00

abstract：:A series of N2-[(acylamino)alkyl]-6,7-dimethoxy-2,4-quinazolinediamines was synthesized as potential alpha 1-adrenoceptor antagonists. When administered to spontaneously hypertensive rats at 10 mg/kg po, a number of propanediamine derivatives showed good antihypertensive activity, whereas the ethanediamine derivatives...

journal_title：Journal of medicinal chemistry

authors： Manoury PM,Binet JL,Dumas AP,Lefèvre-Borg F,Cavero I

更新日期：1986-01-01 00:00:00

abstract：:The chemical synthesis and structure-activity relationships of a novel series of 17beta-glucocorticoid butyrolactones possessing either a 16alpha,17alpha-isopropylidene or -butylidene group are described. The sulfur-linked gamma-lactone group was incorporated onto the 17beta-position of the androstane nucleus via Bart...

journal_title：Journal of medicinal chemistry

authors： Procopiou PA,Biggadike K,English AF,Farrell RM,Hagger GN,Hancock AP,Haase MV,Irving WR,Sareen M,Snowden MA,Solanke YE,Tralau-Stewart CJ,Walton SE,Wood JA

更新日期：2001-02-15 00:00:00

abstract：:Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent γ-ca...

journal_title：Journal of medicinal chemistry

authors： Otto R,Penzis R,Gaube F,Adolph O,Föhr KJ,Warncke P,Robaa D,Appenroth D,Fleck C,Enzensperger C,Lehmann J,Winckler T

更新日期：2015-08-27 00:00:00

abstract：:A novel bitriazolyl acyclonucleoside was discovered to exhibit powerful antiproliferative effects on different cancer cell lines through caspase-dependent apoptosis and at the same time stimulate the immune response in dendritic cells via Toll-like receptor 7 (TLR7) signaling. This promising compound with dual antican...

journal_title：Journal of medicinal chemistry

authors： Xia Y,Wang M,Demaria O,Tang J,Rocchi P,Qu F,Iovanna JL,Alexopoulou L,Peng L

更新日期：2012-06-14 00:00:00

abstract：:A series of N-aryl-N'-(2-chloroethyl)ureas (CEUs) and derivatives were synthesized and evaluated for antiproliferative activity against a wide panel of tumor cell lines. Systematic structure--activity relationship (SAR) studies indicated that: (i) a branched alkyl chain or a halogen at the 4-position of the phenyl rin...

journal_title：Journal of medicinal chemistry

authors： Mounetou E,Legault J,Lacroix J,C-Gaudreault R

更新日期：2001-03-01 00:00:00

abstract：:The alcohol-abuse deterrent disulfiram (DSF) is shown to have a highly selective toxicity against melanoma in culture, inducing a largely apoptotic response, with much lower toxicity against several other cell lines. Melanoma cell lines derived from different stages (radial, vertical, and metastatic phase) were all se...

journal_title：Journal of medicinal chemistry

authors： Cen D,Brayton D,Shahandeh B,Meyskens FL Jr,Farmer PJ

更新日期：2004-12-30 00:00:00

abstract：:When cephalosporins exert their biological activity by reacting with bacterial enzymes, opening of the beta-lactam ring can lead to expulsion of the 3'-substituent. A series of cephalosporins was prepared in which antibacterial quinolones were linked to the 3'-position through a quaternary nitrogen. Like the 3'-ester-...

journal_title：Journal of medicinal chemistry

authors： Albrecht HA,Beskid G,Christenson JG,Durkin JW,Fallat V,Georgopapadakou NH,Keith DD,Konzelmann FM,Lipschitz ER,McGarry DH

更新日期：1991-02-01 00:00:00

abstract：:In the present work, we have designed and synthesized a series of arachidonic acid derivatives of general structure I which have been characterized as highly potent and selective inhibitors of anandamide transporter (IC(50) = 24-0.8 microM, K(i) > 1000-5000 nM for CB(1) and CB(2) cannabinoid receptors and vanilloid VR...

journal_title：Journal of medicinal chemistry

authors： López-Rodríguez ML,Viso A,Ortega-Gutiérrez S,Lastres-Becker I,González S,Fernández-Ruiz J,Ramos JA

更新日期：2001-12-20 00:00:00

abstract：:Although recognized in small molecules for quite some time, the implications of halogen bonding in biomolecular systems are only now coming to light. In this study, several systems of proteins in complex with halogenated ligands have been investigated by using a two-layer QM/MM ONIOM methodology. In all cases, the hal...

journal_title：Journal of medicinal chemistry

authors： Lu Y,Shi T,Wang Y,Yang H,Yan X,Luo X,Jiang H,Zhu W

更新日期：2009-05-14 00:00:00

abstract：:The synthesis and in vitro structure-activity relationships (SAR) of a novel series of anilinoquinazolines as allosteric inhibitors of fructose-1,6-bisphosphatase (F16Bpase) are reported. The compounds have a different SAR as inhibitors of F16Bpase than anilinoquinazolines previously reported. Selective inhibition of ...

journal_title：Journal of medicinal chemistry

authors： Wright SW,Carlo AA,Carty MD,Danley DE,Hageman DL,Karam GA,Levy CB,Mansour MN,Mathiowetz AM,McClure LD,Nestor NB,McPherson RK,Pandit J,Pustilnik LR,Schulte GK,Soeller WC,Treadway JL,Wang IK,Bauer PH

更新日期：2002-08-29 00:00:00

abstract：:The synthesis of the first 4-amino-3-carboxy-beta-carboline derivative (35) is described. This synthesis is based on ozonolysis of the 4-vinyl-beta-carboline-3-carboxamide 17 to give the 4-aldehyde 20 and potassium permanganate oxidation of the latter to the 4-carboxylic acid 34 followed by a DPPA-promoted Curtius rea...

journal_title：Journal of medicinal chemistry

authors： Dorey G,Dubois L,Prodo de Carvalho LP,Potier P,Dodd RH

更新日期：1995-01-06 00:00:00

abstract：:Increasing evidence suggests that iron plays an important role in tissue damage both during chronic iron overload diseases (i.e., hemochromatosis) and when, in the absence of actual tissue iron overload, iron is delocalized from specific carriers or intracellular sites (inflammation, neurodegenerative diseases, postis...

journal_title：Journal of medicinal chemistry

authors： Ferrali M,Bambagioni S,Ceccanti A,Donati D,Giorgi G,Fontani M,Laschi F,Zanello P,Casolaro M,Pietrangelo A

更新日期：2002-12-19 00:00:00

abstract：:Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibi...

journal_title：Journal of medicinal chemistry

authors： Nencka R,Votruba I,Hrebabecký H,Jansa P,Tloust'ová E,Horská K,Masojídková M,Holý A

更新日期：2007-11-29 00:00:00

abstract：:Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for...

journal_title：Journal of medicinal chemistry

authors： Narwal M,Venkannagari H,Lehtiö L

更新日期：2012-02-09 00:00:00

abstract：:Pleuromutilin and its derivatives are antibacterial drugs that inhibit protein synthesis in bacteria by binding to ribosomes. To promote rational design of pleuromutilin based drugs, 19 pleuromutilin conjugates with different nucleoside fragments as side chain extensions were synthesized by a click chemistry protocol....

journal_title：Journal of medicinal chemistry

authors： Lolk L,Pøhlsgaard J,Jepsen AS,Hansen LH,Nielsen H,Steffansen SI,Sparving L,Nielsen AB,Vester B,Nielsen P

更新日期：2008-08-28 00:00:00

abstract：:3-O-tert-Butylmorphine (5) was prepared from 6-O-acetylmorphine (3) via alkylation with N,N-dimethylformamide di-tert-butyl acetal, followed by hydrolytic removal of the 3-(dimethylamino)-2-propenoate group. The same process was used to prepare the tert-butyl ether of levorphanol (6), (-)-3-tert-butoxy-N-methylmorphin...

journal_title：Journal of medicinal chemistry

authors： Mohacsi E,Leimgruber W,Baruth H

更新日期：1982-10-01 00:00:00