Discovery of a neuroprotective chemical, (S)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(-)-P7C3-S243], with improved druglike properties.

abstract：:Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to...

journal_title：Journal of medicinal chemistry

authors： Borišek J,Vizovišek M,Sosnowski P,Turk B,Turk D,Mohar B,Novič M

更新日期：2015-09-10 00:00:00

abstract：:In the treatment of cardiovascular diseases, it could be of therapeutic interest to associate the hypotensive effects resulting from the inhibition of angiotensin II formation, ensured by endothelial angiotensin-converting enzyme (ACE), with the diuretic and natriuretic responses due to the protection of the endogenou...

journal_title：Journal of medicinal chemistry

authors： Fournié-Zaluski MC,Coric P,Turcaud S,Rousselet N,Gonzalez W,Barbe B,Pham I,Jullian N,Michel JB,Roques BP

更新日期：1994-04-15 00:00:00

abstract：:2,5-Dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4' - yl]methyl]-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action. To explore the lipophilic pocket in the AII receptor interacting with the substituent ...

journal_title：Journal of medicinal chemistry

authors： Huang HC,Reitz DB,Chamberlain TS,Olins GM,Corpus VM,McMahon EG,Palomo MA,Koepke JP,Smits GJ,McGraw DE

更新日期：1993-07-23 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：:Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. On the basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, we implemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety to afford tetracy...

journal_title：Journal of medicinal chemistry

authors： Magedov IV,Manpadi M,Slambrouck SV,Steelant WF,Rozhkova E,Przheval'skii NM,Rogelj S,Kornienko A

更新日期：2007-10-18 00:00:00

abstract：:A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactiva...

journal_title：Journal of medicinal chemistry

authors： Yang BV,Weinstein DS,Doweyko LM,Gong H,Vaccaro W,Huynh T,Xiao HY,Doweyko AM,McKay L,Holloway DA,Somerville JE,Habte S,Cunningham M,McMahon M,Townsend R,Shuster D,Dodd JH,Nadler SG,Barrish JC

更新日期：2010-12-09 00:00:00

abstract：:Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Prev...

journal_title：Journal of medicinal chemistry

authors： Das SG,Srinivasan B,Hermanson DL,Bleeker NP,Doshi JM,Tang R,Beck WT,Xing C

更新日期：2011-08-25 00:00:00

abstract：:The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engin...

journal_title：Journal of medicinal chemistry

authors： Barkey NM,Tafreshi NK,Josan JS,De Silva CR,Sill KN,Hruby VJ,Gillies RJ,Morse DL,Vagner J

更新日期：2011-12-08 00:00:00

abstract：:Tethered dimers incorporating natural alpha-amino acid end groups were synthesized, including examples in which the previously reported esterase-sensitive ester linker was replaced with more stable amide or ether linkers. These compounds remained effective both as inhibitors of NAD synthetase and as potent antibacteri...

journal_title：Journal of medicinal chemistry

authors： Velu SE,Mou L,Luan CH,Yang ZW,DeLucas LJ,Brouillette CG,Brouillette WJ

更新日期：2007-05-31 00:00:00

abstract：:A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptos...

journal_title：Journal of medicinal chemistry

authors： Andersen KE,Braestrup C,Grønwald FC,Jørgensen AS,Nielsen EB,Sonnewald U,Sørensen PO,Suzdak PD,Knutsen LJ

更新日期：1993-06-11 00:00:00

abstract：:Previously reported 2-(hydroxymethyl)indoloquinones, prepared as their acetates or carbamates, were less active than 2-methyl analogues in bacterial cultures and they had no activity in mice, despite functionality appropriate for DNA cross-linking. On the basis of the hypothesis that these compounds might have been to...

journal_title：Journal of medicinal chemistry

authors： Iyengar BS,Remers WA,Catino JJ

更新日期：1989-08-01 00:00:00

abstract：:The pyridine C-nucleosides 5-beta-D-ribofuranosylnicotinamide and its N-methylpyridinium derivative (1 and 2), which are isosteric and isoelectronic, respectively, to nicotinamide nucleoside were synthesized. Condensation of 3-bromo-5-lithiopyridine with 2,4:3,5-di-O-benzylidene-D-aldehydoribose (7) afforded an allo/a...

journal_title：Journal of medicinal chemistry

authors： Kabat MM,Pankiewicz KW,Watanabe KA

更新日期：1987-05-01 00:00:00

abstract：:To enhance the ability of indirubin derivatives to inhibit CDK2/cyclin E, a target of anticancer agents, we designed and synthesized a new series of indirubin-3'-oxime derivatives with combined substitutions at the 5 and 5' positions. A molecular docking study predicted the binding of derivatives with OH or halogen su...

journal_title：Journal of medicinal chemistry

authors： Choi SJ,Lee JE,Jeong SY,Im I,Lee SD,Lee EJ,Lee SK,Kwon SM,Ahn SG,Yoon JH,Han SY,Kim JI,Kim YC

更新日期：2010-05-13 00:00:00

abstract：:Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or ary...

journal_title：Journal of medicinal chemistry

authors： von Geldern TW,Kester JA,Bal R,Wu-Wong JR,Chiou W,Dixon DB,Opgenorth TJ

更新日期：1996-02-16 00:00:00

abstract：:Conformational restriction of previously disclosed acyclic (diphenylethyl)diphenylacetamides led to the discovery of several potent inhibitors of acyl CoA:cholesterol acyltransferase (ACAT). cis-[2-(4-Hydroxyphenyl)-1-indanyl]diphenylacetamide (4a) was the most potent ACAT inhibitor identified (IC50 = 0.04 microM in a...

journal_title：Journal of medicinal chemistry

authors： Vaccaro W,Amore C,Berger J,Burrier R,Clader J,Davis H,Domalski M,Fevig T,Salisbury B,Sher R

更新日期：1996-04-12 00:00:00

abstract：:The enantiomers of two isosteric phosphonate analogs of the ether-linked antitumor agent 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OMe) were synthesized and evaluated for their cytotoxicity against various mouse leukemic cell lines in vitro and in vivo. The key step in the synthesis of the alkyloxy a...

journal_title：Journal of medicinal chemistry

authors： Bittman R,Byun HS,Mercier B,Salari H

更新日期：1994-02-04 00:00:00

abstract：:As part of a study on the antitumor activities of tropolone derivatives prepared from hinokitiol, which naturally occurs in the plants of Chamaecyparis species, effects of aromatic substituents of alpha,alpha-bis(7-hydroxy-5-isopropyltropon-2-yl)toluenes on the activity were examined. Several of the compounds showed h...

journal_title：Journal of medicinal chemistry

authors： Yamato M,Hashigaki K,Kokubu N,Tashiro T,Tsuruo T

更新日期：1986-07-01 00:00:00

abstract：:The synthesis and antihypertensive activity of a series of novel 3-[(substituted-carbonyl)amino]-2H-1-benzopyran-4-ols, administered orally to spontaneously hypertensive rats, are described. Optimum activity in this series was observed for compounds with branched alkyl or branched alkylamino groups flanking the carbon...

journal_title：Journal of medicinal chemistry

authors： Cassidy F,Evans JM,Hadley MS,Haladij AH,Leach PE,Stemp G

更新日期：1992-05-01 00:00:00

abstract：:New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaf...

journal_title：Journal of medicinal chemistry

authors： Fletcher S,Cummings CG,Rivas K,Katt WP,Hornéy C,Buckner FS,Chakrabarti D,Sebti SM,Gelb MH,Van Voorhis WC,Hamilton AD

更新日期：2008-09-11 00:00:00

abstract：:Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Criti...

journal_title：Journal of medicinal chemistry

authors： La DS,Belzile J,Bready JV,Coxon A,DeMelfi T,Doerr N,Estrada J,Flynn JC,Flynn SR,Graceffa RF,Harriman SP,Larrow JF,Long AM,Martin MW,Morrison MJ,Patel VF,Roveto PM,Wang L,Weiss MM,Whittington DA,Teffera Y,Zhao Z

更新日期：2008-03-27 00:00:00

abstract：:The synthesis and sigma 1 and sigma 2 binding properties of several (+)- and (-)-2-benzyl- and 2-dimethylallyl-2'-substituted-5,9 alpha-dimethyl-6,7-benzomorphans (3 and 4) are presented. In agreement with previously reported binding data for 2-substituted 5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans (N-substituted...

journal_title：Journal of medicinal chemistry

authors： Danso-Danquah R,Bai X,Zhang X,Mascarella SW,Williams W,Sine B,Bowen WD,Carroll FI

更新日期：1995-07-21 00:00:00

abstract：:The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized ...

journal_title：Journal of medicinal chemistry

authors： Miwatashi S,Arikawa Y,Kotani E,Miyamoto M,Naruo K,Kimura H,Tanaka T,Asahi S,Ohkawa S

更新日期：2005-09-22 00:00:00

abstract：:We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged a...

journal_title：Journal of medicinal chemistry

authors： Gangjee A,Zeng Y,McGuire JJ,Kisliuk RL

更新日期：2005-08-11 00:00:00

abstract：:HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this compound were prepared and ev...

journal_title：Journal of medicinal chemistry

authors： Hrib NJ,Jurcak JG,Bregna DE,Burgher KL,Hartman HB,Kafka S,Kerman LL,Kongsamut S,Roehr JE,Szewczak MR,Woods-Kettelberger AT,Corbett R

更新日期：1996-09-27 00:00:00

abstract：:Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the...

journal_title：Journal of medicinal chemistry

authors： Gao M,Duan L,Luo J,Zhang L,Lu X,Zhang Y,Zhang Z,Tu Z,Xu Y,Ren X,Ding K

更新日期：2013-04-25 00:00:00

abstract：:The thioredoxin system plays an important role in cancer cells. Inhibiting thioredoxin reductase (TrxR) has emerged as an effective strategy to selectively target cancer cells. Withangulatin A (WA), a natural product extracted from the whole herb of Physalis angulata L. (Solanaceae), exhibits potent anticancer activit...

journal_title：Journal of medicinal chemistry

authors： Wang C,Li S,Zhao J,Yang H,Yin F,Ding M,Luo J,Wang X,Kong L

更新日期：2020-10-08 00:00:00

abstract：:As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cyto...

journal_title：Journal of medicinal chemistry

authors： Alverez CN,Park JE,Toti KS,Xia Y,Krausz KW,Rai G,Bang JK,Gonzalez FJ,Jacobson KA,Lee KS

更新日期：2020-11-25 00:00:00

abstract：:As part of an ongoing effort to discover novel small-molecule antifolates combining the enzyme-binding species selectivity of trimethoprim (TMP) with the potency of piritrexim (PTX), 10 previously unreported 2,4-diamino-5-(2'-methoxy-5'-substituted)benzylpyrimidines (2-11) containing a carboxyl group at the distal end...

journal_title：Journal of medicinal chemistry

authors： Rosowsky A,Forsch RA,Queener SF

更新日期：2003-04-24 00:00:00

abstract：:Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based...

journal_title：Journal of medicinal chemistry

authors： Li S,Xu H,Cui S,Wu F,Zhang Y,Su M,Gong Y,Qiu S,Jiao Q,Qin C,Shan J,Zhang M,Wang J,Yin Q,Xu M,Liu X,Wang R,Zhu L,Li J,Xu Y,Jiang H,Zhao Z,Li J,Li H

更新日期：2016-07-28 00:00:00

abstract：:The dihydrochalcone derivatives of the bitter flavonoids naringin and neohesperedin are intensely sweet. Phyllodulcin is as sweet as the dihydrochalcones with similar taste properties although its structure apparently resembles that of bitter flavanone or flavone. Multifaceted approaches, including X-ray crystal struc...

journal_title：Journal of medicinal chemistry

authors： Shin W,Kim SJ,Shin JM,Kim SH

更新日期：1995-10-13 00:00:00