Studies of antitumor agents. 1. Resolution of racemic 1-(tetrahydro-2-furanyl)-k-fluorouracil into the R and S isomers and examination of the biological activities of the isomers.

abstract：:A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3K...

journal_title：Journal of medicinal chemistry

authors： Thakur A,Tawa GJ,Henderson MJ,Danchik C,Liu S,Shah P,Wang AQ,Dunn G,Kabir M,Padilha EC,Xu X,Simeonov A,Kharbanda S,Stone R,Grewal G

更新日期：2020-04-23 00:00:00

abstract：:We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate exp...

journal_title：Journal of medicinal chemistry

authors： Majellaro M,Jespers W,Crespo A,Núñez MJ,Novio S,Azuaje J,Prieto-Díaz R,Gioé C,Alispahic B,Brea J,Loza MI,Freire-Garabal M,Garcia-Santiago C,Rodríguez-García C,García-Mera X,Caamaño O,Fernandez-Masaguer C,Sardina JF,St

更新日期：2021-01-14 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：:A series of analogues of the recently reported angiotensin II (AII) antagonist [Sar1]AII-(1-7)-amide or des-Phe8[Sar1]AII (3) have been prepared by solid-phase synthesis and purified by reverse-phase liquid chromatography. The agonist and antagonist properties of these carboxy-truncated analogues of AII were determine...

journal_title：Journal of medicinal chemistry

authors： Bovy PR,O'Neal JM,Olins GM,Patton DR,McMahon EG,Palomo M,Koepke JP,Salles KS,Trapani AJ,Smits GJ

更新日期：1990-05-01 00:00:00

abstract：:The discovery of a series of novel halogenated arylsulfonamides (HAS) as new sigma receptor binding tumor imaging agents is described. Several substituted halogenated sulfonamides have been prepared and characterized. Target compounds were examined for their affinity for sigma1 and sigma2 receptor subtypes using guine...

journal_title：Journal of medicinal chemistry

authors： John CS,Lim BB,Vilner BJ,Geyer BC,Bowen WD

更新日期：1998-07-02 00:00:00

abstract：:AMPA receptors mediate fast excitatory synaptic transmission and are essential for synaptic plasticity. ANQX, a photoreactive AMPA receptor antagonist, is an important biological probe used to irreversibly inactivate AMPA receptors. Here, using X-ray crystallography and mass spectroscopy, we report that ANQX forms two...

journal_title：Journal of medicinal chemistry

authors： Cruz LA,Estébanez-Perpiñá E,Pfaff S,Borngraeber S,Bao N,Blethrow J,Fletterick RJ,England PM

更新日期：2008-09-25 00:00:00

abstract：:A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expr...

journal_title：Journal of medicinal chemistry

authors： Tafesse L,Kanemasa T,Kurose N,Yu J,Asaki T,Wu G,Iwamoto Y,Yamaguchi Y,Ni C,Engel J,Tsuno N,Patel A,Zhou X,Shintani T,Brown K,Hasegawa T,Shet M,Iso Y,Kato A,Kyle DJ

更新日期：2014-08-14 00:00:00

abstract：:Here, we report the synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu/kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as those the two reference c...

journal_title：Journal of medicinal chemistry

authors： Neumeyer JL,Peng X,Knapp BI,Bidlack JM,Lazarus LH,Salvadori S,Trapella C,Balboni G

更新日期：2006-09-07 00:00:00

abstract：:A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluor...

journal_title：Journal of medicinal chemistry

authors： Higley CA,Wilde RG,Maduskuie TP,Johnson AL,Pennev P,Billheimer JT,Robinson CS,Gillies PJ,Wexler RR

更新日期：1994-10-14 00:00:00

abstract：:Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC5...

journal_title：Journal of medicinal chemistry

authors： Liu J,Zheng S,Akerstrom VL,Yuan C,Ma Y,Zhong Q,Zhang C,Zhang Q,Guo S,Ma P,Skripnikova EV,Bratton MR,Pannuti A,Miele L,Wiese TE,Wang G

更新日期：2016-09-08 00:00:00

abstract：:A series of novel nitroheterocyclic phosphoramidates has been evaluated for antitumor activity in murine and xenograft tumor models and for toxicity in mice. Significant increases in lifespan and long-term survivors were noted in L1210 leukemia and B16 melanoma models, and both complete and partial tumor regressions w...

journal_title：Journal of medicinal chemistry

authors： Borch RF,Liu J,Joswig C,Baggs RB,Dexter DL,Mangold GL

更新日期：2001-01-04 00:00:00

abstract：:Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a novel and attractive approach to reduce the local levels of the active estrogen 17β-estradiol in patients with estrogen-dependent diseases like breast cancer or endometriosis. With the aim of optimizing the biological profile of 17β-HSD1 inhibitors ...

journal_title：Journal of medicinal chemistry

authors： Marchais-Oberwinkler S,Wetzel M,Ziegler E,Kruchten P,Werth R,Henn C,Hartmann RW,Frotscher M

更新日期：2011-01-27 00:00:00

abstract：:The synthesis of 2-amino-2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene is reported. This compound did not produce vasodilation in the dog renal artery and was inactive as a DA1-type dopamine agonist. This is in contrast to the 2-nonmethylated homologue 6,7-ADTN, which is a potent DA1 agonist. High-field 1H NMR ...

journal_title：Journal of medicinal chemistry

authors： Nichols DE,Jacob JN,Hoffman AJ,Kohli JD,Glock D

更新日期：1984-12-01 00:00:00

abstract：:EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR i...

journal_title：Journal of medicinal chemistry

authors： Hao Y,Wang X,Zhang T,Sun D,Tong Y,Xu Y,Chen H,Tong L,Zhu L,Zhao Z,Chen Z,Ding J,Xie H,Xu Y,Li H

更新日期：2016-08-11 00:00:00

abstract：:A GABA(A) receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-norallopregnanolone (i.e., 3alpha-hydroxy-7-nor-5alpha-pregnan-20-one) was found comparable to allopregnanolone when measured with labeled TBPS. Analogous results were obtained from their effect on neurons ...

journal_title：Journal of medicinal chemistry

authors： Suñol C,García DA,Bujons J,Kristofíková Z,Matyás L,Babot Z,Kasal A

更新日期：2006-06-01 00:00:00

abstract：:A variety of dicarboxylic acid linkers introduced between the alpha-amino group of Pro(6) and the -amino group of Lys(10) of the cyclic lactam alpha-melanocyte-stimulating hormone (alpha-MSH)-derived Pro(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2 pentapeptide template lead to nanomolar range and selective hMC3...

journal_title：Journal of medicinal chemistry

authors： Mayorov AV,Cai M,Palmer ES,Dedek MM,Cain JP,Van Scoy AR,Tan B,Vagner J,Trivedi D,Hruby VJ

更新日期：2008-01-24 00:00:00

abstract：:A new class of acyclic adenosine analogues is described which exhibit broad-spectrum antiviral activity and are apparently targeted at S-adenosyl-L-homocysteine hydrolase. The compounds are all alkyl (i.e., methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl, tert-butyl, 1-pentyl, 3-methylbutyl, 1-octy...

journal_title：Journal of medicinal chemistry

authors： De Clercq E,Holý A

更新日期：1985-03-01 00:00:00

abstract：:Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation o...

journal_title：Journal of medicinal chemistry

authors： Perez M,Lamothe M,Maraval C,Mirabel E,Loubat C,Planty B,Horn C,Michaux J,Marrot S,Letienne R,Pignier C,Bocquet A,Nadal-Wollbold F,Cussac D,de Vries L,Le Grand B

更新日期：2009-10-08 00:00:00

abstract：:Following the recent discoveries that some L-nucleosides are more or equal potent than their D-counterparts, we synthesized 2'-deoxy-2',2'-difluoro-L-erythro-pentofuranosyl nucleosides as potential antiviral agents. The target compounds were synthesized via the key intermediates 7a or 7b from L-gulono gamma-lactone. C...

journal_title：Journal of medicinal chemistry

authors： Kotra LP,Xiang Y,Newton MG,Schinazi RF,Cheng YC,Chu CK

更新日期：1997-10-24 00:00:00

abstract：:Lipophilicity/bioavailibility of Mn(III) N-alkylpyridylporphyrin-based superoxide dismutase (SOD) mimics has a major impact on their in vivo ability to suppress oxidative stress. Meta isomers are less potent SOD mimics than ortho analogues but are 10-fold more lipophilic and more planar. Enhanced lipophilicity contrib...

journal_title：Journal of medicinal chemistry

authors： Kos I,Benov L,Spasojević I,Rebouças JS,Batinić-Haberle I

更新日期：2009-12-10 00:00:00

abstract：:(+/-)-7-Aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline (7) is one of the most potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) reported to date, but a blood-brain barrier (BBB) model indicates that it cannot penetrate the BBB. To increase the lipophilicity of 7 by addition ...

journal_title：Journal of medicinal chemistry

authors： Romero FA,Vodonick SM,Criscione KR,McLeish MJ,Grunewald GL

更新日期：2004-08-26 00:00:00

abstract：:The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically a...

journal_title：Journal of medicinal chemistry

authors： Li H,Huang Q,Chen C,Xu B,Wang HY,Long YQ

更新日期：2017-04-13 00:00:00

abstract：:Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This m...

journal_title：Journal of medicinal chemistry

authors： Hale JJ,Mills SG,MacCoss M,Finke PE,Cascieri MA,Sadowski S,Ber E,Chicchi GG,Kurtz M,Metzger J,Eiermann G,Tsou NN,Tattersall FD,Rupniak NM,Williams AR,Rycroft W,Hargreaves R,MacIntyre DE

更新日期：1998-11-05 00:00:00

abstract：:Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical prop...

journal_title：Journal of medicinal chemistry

authors： Koeberle SC,Fischer S,Schollmeyer D,Schattel V,Grütter C,Rauh D,Laufer SA

更新日期：2012-06-28 00:00:00

abstract：:Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addre...

journal_title：Journal of medicinal chemistry

authors： Moreau B,O'Meara JA,Bordeleau J,Garneau M,Godbout C,Gorys V,Leblanc M,Villemure E,White PW,Llinàs-Brunet M

更新日期：2014-03-13 00:00:00

abstract：:We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified ...

journal_title：Journal of medicinal chemistry

authors： Henke BR,Blanchard SG,Brackeen MF,Brown KK,Cobb JE,Collins JL,Harrington WW Jr,Hashim MA,Hull-Ryde EA,Kaldor I,Kliewer SA,Lake DH,Leesnitzer LM,Lehmann JM,Lenhard JM,Orband-Miller LA,Miller JF,Mook RA Jr,Noble SA,Ol

更新日期：1998-12-03 00:00:00

abstract：:Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC(50) and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position an...

journal_title：Journal of medicinal chemistry

authors： Kim P,Zhang YM,Shenoy G,Nguyen QA,Boshoff HI,Manjunatha UH,Goodwin MB,Lonsdale J,Price AC,Miller DJ,Duncan K,White SW,Rock CO,Barry CE 3rd,Dowd CS

更新日期：2006-01-12 00:00:00

abstract：:A three-dimensional model of the AT1 receptor was constructed by means of a homology modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template and taking into account the available site-directed mutagenesis data. The docking of losartan and its active metabolite EXP3174, followed by 1 n...

journal_title：Journal of medicinal chemistry

authors： Tuccinardi T,Calderone V,Rapposelli S,Martinelli A

更新日期：2006-07-13 00:00:00

abstract：:Recently we reported the synthesis of the first enantiomeric pair of irreversible opioid ligands [(3S,4R)-(-)- and (3R,4S)-(+)-cis-4, SUPERFIT] and specific interaction of the latter with the delta receptor. Here we report another enantiomeric pair of irreversible opioid ligands, (+)-trans- and (-)-trans-3-methylfenta...

journal_title：Journal of medicinal chemistry

authors： Kim CH,Rothman RB,Jacobson AE,Mattson MV,Bykov V,Streaty RA,Klee WA,George C,Long JB,Rice KC

更新日期：1989-06-01 00:00:00

abstract：:Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of ...

journal_title：Journal of medicinal chemistry

authors： Duque MD,Ma C,Torres E,Wang J,Naesens L,Juárez-Jiménez J,Camps P,Luque FJ,DeGrado WF,Lamb RA,Pinto LH,Vázquez S

更新日期：2011-04-28 00:00:00