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：:Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly...

journal_title：Journal of medicinal chemistry

authors： Meijer FA,Doveston RG,de Vries RMJM,Vos GM,Vos AAA,Leysen S,Scheepstra M,Ottmann C,Milroy LG,Brunsveld L

更新日期：2020-01-09 00:00:00

abstract：:New transition-state analogues bearing C-termini derived from alpha-mercaptoalkanoic acids, esters, and amides were prepared and evaluated as inhibitors of human renin. Addition of alpha-mercaptoalkanoate esters to a chiral Boc-amino epoxide intermediate led ultimately to the target [(2R,3S)-3-(BocPheHis-amino)-4-cycl...

journal_title：Journal of medicinal chemistry

authors： Ashton WT,Cantone CL,Tolman RL,Greenlee WJ,Lynch RJ,Schorn TW,Strouse JF,Siegl PK

更新日期：1992-07-24 00:00:00

abstract：:Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral ...

journal_title：Journal of medicinal chemistry

authors： Pizzirani D,Pagliuca C,Realini N,Branduardi D,Bottegoni G,Mor M,Bertozzi F,Scarpelli R,Piomelli D,Bandiera T

更新日期：2013-05-09 00:00:00

abstract：:The 2S,3S and 2R,3S diastereoisomers of the hydroxy amino acid 3-amino-2-hydroxy-5-methylhexanoic acid (AHMHA) were synthesized and substituted for the leucyl residues of Leu-Leu-Val-Phe-OCH3 to yield the following analogues: AHMHA-Leu-Val-Phe-OCH3, AHMHA-Val-Phe-OCH3, and Leu-AHMHA-Val-Phe-OCH3. These analogues were ...

journal_title：Journal of medicinal chemistry

authors： Johnson RL

更新日期：1982-05-01 00:00:00

abstract：:The coupling of two different pharmacophores, each endowed with different biological properties, afforded the hybrid compound lipocrine (7), whose biological profile was markedly improved relative to those of prototypes tacrine and lipoic acid. Lipocrine is the first compound that inhibits the catalytic activity of AC...

journal_title：Journal of medicinal chemistry

authors： Rosini M,Andrisano V,Bartolini M,Bolognesi ML,Hrelia P,Minarini A,Tarozzi A,Melchiorre C

更新日期：2005-01-27 00:00:00

abstract：:The new pyrimidine derivatives of 2,3-O, O-dibenzyl-6-deoxy-L-ascorbic acid (8-10) were synthesized by condensation of uracil and its 5-fluoro- and 5-trifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2, 3-O,O-dibenzyl-L-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5,6-dideoxy-L-ascor...

journal_title：Journal of medicinal chemistry

authors： Raić-Malić S,Svedruzić D,Gazivoda T,Marunović A,Hergold-Brundić A,Nagl A,Balzarini J,De Clercq E,Mintas M

更新日期：2000-12-14 00:00:00

abstract：:The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms...

journal_title：Journal of medicinal chemistry

authors： Pirali T,Serafini M,Cargnin S,Genazzani AA

更新日期：2019-06-13 00:00:00

abstract：:The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2...

journal_title：Journal of medicinal chemistry

authors： Andersson CD,Karlberg T,Ekblad T,Lindgren AE,Thorsell AG,Spjut S,Uciechowska U,Niemiec MS,Wittung-Stafshede P,Weigelt J,Elofsson M,Schüler H,Linusson A

更新日期：2012-09-13 00:00:00

abstract：:Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazol...

journal_title：Journal of medicinal chemistry

authors： Furlotti G,Alisi MA,Apicella C,Capezzone de Joannon A,Cazzolla N,Costi R,Cuzzucoli Crucitti G,Garrone B,Iacovo A,Magarò G,Mangano G,Miele G,Ombrato R,Pescatori L,Polenzani L,Rosi F,Vitiello M,Di Santo R

更新日期：2012-11-26 00:00:00

abstract：:Acyl carrier protein synthase (AcpS) catalyzes the transfer of the 4'-phosphopantetheinyl group from the coenzyme A to a serine residue in acyl carrier protein (ACP), thereby activating ACP, an important step in cell wall biosynthesis. The structure-based design of novel anthranilic acid inhibitors of AcpS, a potentia...

journal_title：Journal of medicinal chemistry

authors： Joseph-McCarthy D,Parris K,Huang A,Failli A,Quagliato D,Dushin EG,Novikova E,Severina E,Tuckman M,Petersen PJ,Dean C,Fritz CC,Meshulam T,DeCenzo M,Dick L,McFadyen IJ,Somers WS,Lovering F,Gilbert AM

更新日期：2005-12-15 00:00:00

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

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

abstract：:The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-...

journal_title：Journal of medicinal chemistry

authors： Li G,Meanwell NA,Krystal MR,Langley DR,Naidu BN,Sivaprakasam P,Lewis H,Kish K,Khan JA,Ng A,Trainor GL,Cianci C,Dicker IB,Walker MA,Lin Z,Protack T,Discotto L,Jenkins S,Gerritz SW,Pendri A

更新日期：2020-03-12 00:00:00

abstract：:With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 μM for ADP. Furthermore, 7A rescued pr...

journal_title：Journal of medicinal chemistry

authors： Azran S,Danino O,Förster D,Kenigsberg S,Reiser G,Dixit M,Singh V,Major DT,Fischer B

更新日期：2015-11-12 00:00:00

abstract：:Renin inhibitors 2-4 with the D-Lys renin inhibitory peptide (RIP) sequence, but containing Leu psi[CH2O]Ala (2), Leu psi[CH2O]Val (3), and Leu psi[CH2O]Leu (4) at the P1-P1' site, were of a comparable potency to RIP. N-Terminal Boc-protected inhibitors containing Pro psi[CH2O]Phe in positions P4-P3 were potent inhibi...

journal_title：Journal of medicinal chemistry

authors： TenBrink RE,Pals DT,Harris DW,Johnson GA

更新日期：1988-03-01 00:00:00

abstract：:Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand ef...

journal_title：Journal of medicinal chemistry

authors： Crawford TD,Ndubaku CO,Chen H,Boggs JW,Bravo BJ,Delatorre K,Giannetti AM,Gould SE,Harris SF,Magnuson SR,McNamara E,Murray LJ,Nonomiya J,Sambrone A,Schmidt S,Smyczek T,Stanley M,Vitorino P,Wang L,West K,Wu P,Ye W

更新日期：2014-04-24 00:00:00

abstract：:Adverse drug reactions (ADRs) are a common cause of attrition in drug discovery and development and drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug terminations. This perspective outlines many of the known DILI mechanisms and assessment methods used to evaluate and mitigate DILI ri...

journal_title：Journal of medicinal chemistry

authors： Norman BH

更新日期：2020-10-22 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：:Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2. 1]octanes (DBO, 1) plays an essential role in modulating affinity toward mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8...

journal_title：Journal of medicinal chemistry

authors： Vianello P,Albinati A,Pinna GA,Lavecchia A,Marinelli L,Borea PA,Gessi S,Fadda P,Tronci S,Cignarella G

更新日期：2000-06-01 00:00:00

abstract：:Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attr...

journal_title：Journal of medicinal chemistry

authors： Kounde CS,Tate EW

更新日期：2020-12-24 00:00:00

abstract：:Several candidate retinoid antagonists were designed on the basis of the ligand superfamily concept and synthesized. Retinoidal activities of these benzimidazole and benzodiazepine derivatives were examined by assay of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. The parent benzim...

journal_title：Journal of medicinal chemistry

authors： Eyrolles L,Kagechika H,Kawachi E,Fukasawa H,Iijima T,Matsushima Y,Hashimoto Y,Shudo K

更新日期：1994-05-13 00:00:00

abstract：:The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete co...

journal_title：Journal of medicinal chemistry

authors： Inoue A,Kawai T,Wakita M,Iimura Y,Sugimoto H,Kawakami Y

更新日期：1996-10-25 00:00:00

abstract：:The preparation of stable complexes between the N7-[2-(2-pyridyl)ethyl] and N7-(2-piperazinylethyl) derivatives of mitomycin C and metal ions such as Cu(II), Zn(II), and Pt(II) was accomplished. Mitomycin C did not form stable complexes, but it rearranged to a mitosene capable of complex formation. Some of these compl...

journal_title：Journal of medicinal chemistry

authors： Iyengar BS,Takahashi T,Remers WA,Bradner WT

更新日期：1986-01-01 00:00:00

abstract：:1-(Tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU), which is named Ftorafur or FT-207 and is used clinically as an antitumor agent, was conveniently synthesized by condensation of the trimethylsilyl derivative of 5-fluorouracil with 2-acetoxytetrahydrofuran using NaI as a catalyst. This optically inactive Thf-FU was res...

journal_title：Journal of medicinal chemistry

authors： Yasumoto M,Moriyama A,Unemi N,Hashimoto S,Suzue T

更新日期：1977-12-01 00:00:00

abstract：:Structural genomics will yield an immense number of protein three-dimensional structures in the near future. Automated theoretical methodologies are needed to exploit this information and are likely to play a pivotal role in drug discovery. Here, we present a fully automated, efficient docking methodology that does no...

journal_title：Journal of medicinal chemistry

authors： Glick M,Grant GH,Richards WG

更新日期：2002-10-10 00:00:00

abstract：:Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity...

journal_title：Journal of medicinal chemistry

authors： Cao JJ,Zheng Y,Wu XW,Tan CP,Chen MH,Wu N,Ji LN,Mao ZW

更新日期：2019-04-11 00:00:00

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

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

abstract：:The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; th...

journal_title：Journal of medicinal chemistry

authors： Del Bello F,Mattioli L,Ghelfi F,Giannella M,Piergentili A,Quaglia W,Cardinaletti C,Perfumi M,Thomas RJ,Zanelli U,Marchioro C,Dal Cin M,Pigini M

更新日期：2010-11-11 00:00:00

abstract：:A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4-dihydroxychalcones wit...

journal_title：Journal of medicinal chemistry

authors： Sogawa S,Nihro Y,Ueda H,Izumi A,Miki T,Matsumoto H,Satoh T

更新日期：1993-11-26 00:00:00

abstract：:3',5'-Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger that regulates numerous biological processes under physiological and pathological conditions, including cancer, diabetes, heart failure, inflammation, and neurological disorders. In the past, all effects of cAMP were initially believed to be med...

journal_title：Journal of medicinal chemistry

authors： Chen H,Wild C,Zhou X,Ye N,Cheng X,Zhou J

更新日期：2014-05-08 00:00:00

abstract：:Sepsis, which is a systemic inflammatory response that follows a bacterial infection, has a high mortality rate and limited therapeutic options. Here we show that the antimicrobial peptide OH-CATH30, which naturally occurs in snake, selectively regulates the innate immune response to protect mice from lethal sepsis. T...

journal_title：Journal of medicinal chemistry

authors： Li SA,Xiang Y,Wang YJ,Liu J,Lee WH,Zhang Y

更新日期：2013-11-27 00:00:00