Semi-rational design of (north)-methanocarba nucleosides as dual acting A(1) and A(3) adenosine receptor agonists: novel prototypes for cardioprotection.

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：:The linear interaction energy method with continuum electrostatics (LIECE) is evaluated in depth on five kinases. The two multiplicative coefficients for the van der Waals energy and electrostatic free energy are shown to be transferable among different kinases. Moreover, good enrichment factors are obtained for a lib...

journal_title：Journal of medicinal chemistry

authors： Kolb P,Huang D,Dey F,Caflisch A

更新日期：2008-03-13 00:00:00

abstract：:Comparative binding energy analysis, a technique to derive receptor-based three-dimensional quantitative structure-activity relationships (3D-QSAR), is herein extended to consider both affinity and selectivity in the derivation of the QSAR model. The extension is based on allowing multiple structurally related recepto...

journal_title：Journal of medicinal chemistry

authors： Murcia M,Morreale A,Ortiz AR

更新日期：2006-10-19 00:00:00

abstract：:A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent ...

journal_title：Journal of medicinal chemistry

authors： Giorgi-Renault S,Renault J,Gebel-Servolles P,Baron M,Paoletti C,Cros S,Bissery MC,Lavelle F,Atassi G

更新日期：1991-01-01 00:00:00

abstract：:Avermectins A2a, B1a, and B2a (1, 2, and 3) were acetylated to give 4"- and 23-acetates 4 and 5 and 4",23-diacetate 6 from 1, the 4"-and 5-acetates 7 and 8 and 4",5-diacetate 9 from 2, and triacetate 10 from 3. Structure proof by 300-MHz 1H NMR and mass spectral fragmentation is discussed for 10. Forcing acetylation c...

journal_title：Journal of medicinal chemistry

authors： Mrozik H,Eskola P,Fisher MH,Egerton JR,Cifelli S,Ostlind DA

更新日期：1982-06-01 00:00:00

abstract：:The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,...

journal_title：Journal of medicinal chemistry

authors： Bélanger PC,Scheigetz J,Young RN,Charleson SE,Hudgin RL,Engelhardt EL

更新日期：1981-11-01 00:00:00

abstract：:Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of ...

journal_title：Journal of medicinal chemistry

authors： Acker TM,Khatri A,Vance KM,Slabber C,Bacsa J,Snyder JP,Traynelis SF,Liotta DC

更新日期：2013-08-22 00:00:00

abstract：:Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be imp...

journal_title：Journal of medicinal chemistry

authors： Staben ST,Feng JA,Lyle K,Belvin M,Boggs J,Burch JD,Chua CC,Cui H,DiPasquale AG,Friedman LS,Heise C,Koeppen H,Kotey A,Mintzer R,Oh A,Roberts DA,Rouge L,Rudolph J,Tam C,Wang W,Xiao Y,Young A,Zhang Y,Hoeflich K

更新日期：2014-02-13 00:00:00

abstract：:As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N(6)-, 2-amino-N(6)-, and N(2)-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate ki...

journal_title：Journal of medicinal chemistry

authors： Bressi JC,Choe J,Hough MT,Buckner FS,Van Voorhis WC,Verlinde CL,Hol WG,Gelb MH

更新日期：2000-11-02 00:00:00

abstract：:A new paradigm for drug research has emerged, namely the deliberate search for molecules able to selectively affect the proliferation, differentiation, and migration of adult stem cells within the tissues in which they exist. Recently, there has been significant interest in medicinal chemistry toward the discovery and...

journal_title：Journal of medicinal chemistry

authors： Davies SG,Kennewell PD,Russell AJ,Seden PT,Westwood R,Wynne GM

更新日期：2015-04-09 00:00:00

abstract：:Multivalent ligands are promising pharmacological tools that may be more efficacious for several diseases than highly selective single-target drugs. A combined therapy using dopaminergic agonists and adenosinergic antagonists is currently being evaluated for the treatment of Parkinson's disease. [(a) Kanda, T.; et al....

journal_title：Journal of medicinal chemistry

authors： Vendrell M,Angulo E,Casadó V,Lluis C,Franco R,Albericio F,Royo M

更新日期：2007-06-28 00:00:00

abstract：:Two routes for the synthesis of 6-substtituted 8-azaguanosine analogues are described. 2,5,6-Triamino-4(3H)-pyrimidinethione (1) was converted by methylation, nitrosation, and acetylation to -n-acetyl-7-(methylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-5-amine (5). The reaction of 5 with 2,3,5-tri-O-acetyl-D-ribofuranosy...

journal_title：Journal of medicinal chemistry

authors： Elliot RD,Montgomery JA

更新日期：1976-10-01 00:00:00

abstract：:The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on th...

journal_title：Journal of medicinal chemistry

authors： Janssens F,Torremans J,Janssen M,Stokbroekx RA,Luyckx M,Janssen PA

更新日期：1985-12-01 00:00:00

abstract：:We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine h...

journal_title：Journal of medicinal chemistry

authors： Lin FY,Liu YL,Li K,Cao R,Zhu W,Axelson J,Pang R,Oldfield E

更新日期：2012-05-10 00:00:00

abstract：:The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of poten...

journal_title：Journal of medicinal chemistry

authors： Drew SL,Thomas-Tran R,Beatty JW,Fournier J,Lawson KV,Miles DH,Mata G,Sharif EU,Yan X,Mailyan AK,Ginn E,Chen J,Wong K,Soni D,Dhanota P,Chen PY,Shaqfeh SG,Meleza C,Pham AT,Chen A,Zhao X,Banuelos J,Jin L,Schind

更新日期：2020-10-08 00:00:00

abstract：:The synthesis and biological evaluation of three classes of chain-modified derivatives of (+)-EHNA are described. Among the 5', 6'-unsaturated derivatives, the Z-isomer was the most potent inhibitor of adenosine deaminase (ADA) but 3-fold less active than (+)-EHNA. Several 9-aralkyladenines (ARADs) have been prepared,...

journal_title：Journal of medicinal chemistry

authors： Pragnacharyulu PV,Varkhedkar V,Curtis MA,Chang IF,Abushanab E

更新日期：2000-11-30 00:00:00

abstract：:Mono- and diphenylpyridazine ureido derivatives, structurally related to DuP 128, were synthesized and tested for their inhibitory activity against ACAT isolated from rat liver microsomes. Several compounds displayed ACAT inhibition in the micromolar range. The amino derivatives 4a-c were also tested against hACAT-1 a...

journal_title：Journal of medicinal chemistry

authors： Gelain A,Bettinelli I,Barlocco D,Kwon BM,Jeong TS,Cho KH,Toma L

更新日期：2005-12-01 00:00:00

abstract：:Ten analogues of the highly mu-receptor selective cyclic opioid peptide H-Tyr-D-Orn-Phe-Asp-NH2 (1) were synthesized by the solid phase method and were characterized in vitro in mu- and delta-receptor representative binding assays and bioassays. These cyclic analogues are structurally related to the linear opioid pept...

journal_title：Journal of medicinal chemistry

authors： Schiller PW,Nguyen TM,Maziak LA,Wilkes BC,Lemieux C

更新日期：1987-11-01 00:00:00

abstract：:In only four chemical steps from naturally occurring artemisinin (1), trioxane dimers 6 and 7 were prepared on a multigram scale in overall 32-44% yields. In mice, both isonicotinate N-oxide dimer 6 and isobutyric acid dimer 7 were considerably more antimalarially efficacious than clinically used sodium artesunate (2)...

journal_title：Journal of medicinal chemistry

authors： Posner GH,McRiner AJ,Paik IH,Sur S,Borstnik K,Xie S,Shapiro TA,Alagbala A,Foster B

更新日期：2004-02-26 00:00:00

abstract：:1-(2-Phenoxyethyl)-1H-imidazole was found to be an inhibitor of thromboxane (TxA2) synthetase, but it also inhibited the adrenal cytochrome P-450 enzyme steroid 11 beta-hydroxylase. The preparation of a series of analogues is described, and activity against TxA2 synthetase, PGI2 synthetase, cyclooxygenase, and steroid...

journal_title：Journal of medicinal chemistry

authors： Cross PE,Dickinson RP,Parry MJ,Randall MJ

更新日期：1985-10-01 00:00:00

abstract：:Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR rever...

journal_title：Journal of medicinal chemistry

authors： Huff SE,Mohammed FA,Yang M,Agrawal P,Pink J,Harris ME,Dealwis CG,Viswanathan R

更新日期：2018-02-08 00:00:00

abstract：:A library of approximately 2000 small molecules biased toward inhibition of histone deacetylases was assayed for antimalarial activity in a high-throughput P. falciparum viability assay. Active compounds were cross-analyzed for induction of histone hyperacetylation in a human myeloma cell line to identify HDAC inhibit...

journal_title：Journal of medicinal chemistry

authors： Patel V,Mazitschek R,Coleman B,Nguyen C,Urgaonkar S,Cortese J,Barker RH,Greenberg E,Tang W,Bradner JE,Schreiber SL,Duraisingh MT,Wirth DF,Clardy J

更新日期：2009-04-23 00:00:00

abstract：:The iodinated analogue of 1-[2-(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP), IPAPP (4), and the corresponding azido compound azido-IPAPP (5) were synthesized. The corresponding no-carrier-added 125I (T1/2 = 60 days, 35-60 keV) labeled compounds were also prepared. High specific binding was obse...

journal_title：Journal of medicinal chemistry

authors： Chumpradit S,Kung HF,Billings J,Guo YZ,Wu Y,Shih J

更新日期：1989-03-01 00:00:00

abstract：:The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailabilit...

journal_title：Journal of medicinal chemistry

authors： Tagat JR,McCombie SW,Nazareno D,Labroli MA,Xiao Y,Steensma RW,Strizki JM,Baroudy BM,Cox K,Lachowicz J,Varty G,Watkins R

更新日期：2004-05-06 00:00:00

abstract：:Novel N,N-disubstituted indol-3-ylglyoxylamides (1-56), bearing different combinations of substituents R 1-R 5, were synthesized and evaluated as ligands of the translocator protein (TSPO), the 18 kDa protein representing the minimal functional unit of the "peripheral-type benzodiazepine receptor" (PBR). Most of the n...

journal_title：Journal of medicinal chemistry

authors： Da Settimo F,Simorini F,Taliani S,La Motta C,Marini AM,Salerno S,Bellandi M,Novellino E,Greco G,Cosimelli B,Da Pozzo E,Costa B,Simola N,Morelli M,Martini C

更新日期：2008-09-25 00:00:00

abstract：:A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC(50) = 0.2-2.3 μM) were more potent than the corresponding monosubstituted N(4)-fatty acyl (EC(50) = 0.4-29....

journal_title：Journal of medicinal chemistry

authors： Agarwal HK,Chhikara BS,Hanley MJ,Ye G,Doncel GF,Parang K

更新日期：2012-05-24 00:00:00

abstract：:P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P b...

journal_title：Journal of medicinal chemistry

authors： Kumar TS,Zhou SY,Joshi BV,Balasubramanian R,Yang T,Liang BT,Jacobson KA

更新日期：2010-03-25 00:00:00

abstract：:We present Fleksy, a new approach to consider both ligand and receptor flexibility in small molecule docking. Pivotal to our method is the use of a receptor ensemble to describe protein flexibility. To construct these ensembles, we use a backbone-dependent rotamer library and implement the concept of interaction sampl...

journal_title：Journal of medicinal chemistry

authors： Nabuurs SB,Wagener M,de Vlieg J

更新日期：2007-12-27 00:00:00

abstract：:Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction networ...

journal_title：Journal of medicinal chemistry

authors： Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z

更新日期：2020-11-25 00:00:00

abstract：:A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy as...

journal_title：Journal of medicinal chemistry

authors： Chantigny YA,Murray JC,Kleinman EF,Robinson RP,Plotkin MA,Reese MR,Buckbinder L,McNiff PA,Millham ML,Schaefer JF,Abramov YA,Bordner J

更新日期：2015-03-26 00:00:00