Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly sele

abstract：:A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED(50) = 3.5 microg, a value about 3-fold higher wi...

journal_title：Journal of medicinal chemistry

authors： Biancalani C,Giovannoni MP,Pieretti S,Cesari N,Graziano A,Vergelli C,Cilibrizzi A,Di Gianuario A,Colucci M,Mangano G,Garrone B,Polenzani L,Dal Piaz V

更新日期：2009-12-10 00:00:00

abstract：:The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors mu, kappa, delta), with 14-phenylpropoxym...

journal_title：Journal of medicinal chemistry

authors： Schütz J,Spetea M,Koch M,Aceto MD,Harris LS,Coop A,Schmidhammer H

更新日期：2003-09-11 00:00:00

abstract：:4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved a...

journal_title：Journal of medicinal chemistry

authors： Seiler MP,Floersheim P,Markstein R,Widmer A

更新日期：1993-04-16 00:00:00

abstract：:Fifteen 7-substituted 4-hydroxyquinoline-3-carboxylic acids have been designed to minimize covariance between the physicochemical substituent parameters: pi, MR, and sigmap. The molecules have been synthesized and evaluated for their ability to inhibit the respiration of Ehrlich ascites cells as a whole cell model and...

journal_title：Journal of medicinal chemistry

authors： Shah KJ,Coats EA

更新日期：1977-08-01 00:00:00

abstract：:In an attempt to rationalize the inability of phenolic benzocycloheptenylamines to activate dopamine (DA) D2 receptors, we have studied the conformational preferences and topography of 6,7,8,9-tetrahydro-1-hydroxy-N,N-dipropyl-5H-benzocyclohepten-6-++ +ylamine (1). Preferred conformations of 1 have been defined by use...

journal_title：Journal of medicinal chemistry

authors： Karlén A,Helander A,Kenne L,Hacksell U

更新日期：1989-04-01 00:00:00

abstract：:A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended dire...

journal_title：Journal of medicinal chemistry

authors： Primofiore G,Da Settimo F,Taliani S,Marini AM,La Motta C,Novellino E,Greco G,Gesi M,Trincavelli L,Martini C

更新日期：2000-01-13 00:00:00

abstract：:The enantiomers of the leukotriene D4 antagonist 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (L-660,711)(MK-571) have been prepared, their absolute stereochemistry has been assigned as S for (+)-1 and R for (-)-1 by X-ray analysis of a synthetic...

journal_title：Journal of medicinal chemistry

authors： Gauthier JY,Jones T,Champion E,Charette L,Dehaven R,Ford-Hutchinson AW,Hoogsteen K,Lord A,Masson P,Piechuta H

更新日期：1990-10-01 00:00:00

abstract：:The ortho hydroxy/methyl, hydroxy/hydroxymethyl, hydroxy/formyl, and hydroxy/carboxy substitution patterns, some of which confer dopaminergic agonist effects upon 2-aminotetralin ring systems, have been incorporated into beta-phenethylamine, 2-aminoindan, and trans-octahydrobenzo[f]quinoline rings. Certain of the 2-am...

journal_title：Journal of medicinal chemistry

authors： Cannon JG,Furlano DC,Dushin RG,Chang YA,Baird SR,Soliman LN,Flynn JR,Long JP,Bhatnagar RK

更新日期：1986-10-01 00:00:00

abstract：:Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening...

journal_title：Journal of medicinal chemistry

authors： Sheppard GS,Wang J,Kawai M,Fidanze SD,BaMaung NY,Erickson SA,Barnes DM,Tedrow JS,Kolaczkowski L,Vasudevan A,Park DC,Wang GT,Sanders WJ,Mantei RA,Palazzo F,Tucker-Garcia L,Lou P,Zhang Q,Park CH,Kim KH,Petros A,Ol

更新日期：2006-06-29 00:00:00

abstract：:17β-HSD14 is a SDR enzyme able to oxidize estradiol and 5-androstenediol using NAD(+). We determined the crystal structure of this human enzyme as the holo form and as ternary complexes with estrone and with the first potent, nonsteroidal inhibitor. The structures reveal a conical, rather large and lipophilic binding ...

journal_title：Journal of medicinal chemistry

authors： Bertoletti N,Braun F,Lepage M,Möller G,Adamski J,Heine A,Klebe G,Marchais-Oberwinkler S

更新日期：2016-07-28 00:00:00

abstract：:2'-Deoxy-2'-isocyano-1-beta-D-arabinofuranosylcytosine (8, NCDAC) has been synthesized as a potential antitumor antimetabolite from a corresponding 2'-azido-2'-deoxy-1-beta-D-arabinofuranosyluracil derivative 2a. Uracil and thymine analogues 6a and 6b of 8 were also prepared. Attempts to synthesize 2'-deoxy-2'-isocyan...

journal_title：Journal of medicinal chemistry

authors： Matsuda A,Dan A,Minakawa N,Tregear SJ,Okazaki S,Sugimoto Y,Sasaki T

更新日期：1993-12-24 00:00:00

abstract：:Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromati...

journal_title：Journal of medicinal chemistry

authors： Bouché L,Christ CD,Siegel S,Fernández-Montalván AE,Holton SJ,Fedorov O,Ter Laak A,Sugawara T,Stöckigt D,Tallant C,Bennett J,Monteiro O,Díaz-Sáez L,Siejka P,Meier J,Pütter V,Weiske J,Müller S,Huber KVM,Hartung IV,H

更新日期：2017-05-11 00:00:00

abstract：:A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2...

journal_title：Journal of medicinal chemistry

authors： Kumar R,Wiebe LI,Hall TW,Knaus EE,Tovell DR,Tyrrell DL,Allen TM,Fathi-Afshar R

更新日期：1989-05-01 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：:A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the mos...

journal_title：Journal of medicinal chemistry

authors： Geratz JD,Mar EC,Loeffler LJ,Fox LB

更新日期：1975-03-01 00:00:00

abstract：:Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in the cytosolic solubilization of fatty acids during fat absorption. In the current studies, the interaction of L-FABP with a range of lipophilic drugs has been evaluated to explore the potential for L-FABP to provide an ...

journal_title：Journal of medicinal chemistry

authors： Chuang S,Velkov T,Horne J,Porter CJ,Scanlon MJ

更新日期：2008-07-10 00:00:00

abstract：:We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterifi...

journal_title：Journal of medicinal chemistry

authors： McGuigan C,Madela K,Aljarah M,Bourdin C,Arrica M,Barrett E,Jones S,Kolykhalov A,Bleiman B,Bryant KD,Ganguly B,Gorovits E,Henson G,Hunley D,Hutchins J,Muhammad J,Obikhod A,Patti J,Walters CR,Wang J,Vernachio J,Ra

更新日期：2011-12-22 00:00:00

abstract：:A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine ( 5) were synthesized and biologically evaluated as A 3 adenosine receptor (A 3 AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A 3 AR, which had bee...

journal_title：Journal of medicinal chemistry

authors： Cosimelli B,Greco G,Ehlardo M,Novellino E,Da Settimo F,Taliani S,La Motta C,Bellandi M,Tuccinardi T,Martinelli A,Ciampi O,Trincavelli ML,Martini C

更新日期：2008-03-27 00:00:00

abstract：:SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis. It is a prodrug of 4-(2, 2-dimethyl-1-oxopropyl)benzoic acid (2) and 4-(2, 2-dimethyl-1-hydroxypropyl)benzoic acid (3), which sequester coenzyme A (CoA) in the mitochondria, and inhibits medium-chain acyltransferase. 1-3 a...

journal_title：Journal of medicinal chemistry

authors： Aicher TD,Bebernitz GR,Bell PA,Brand LJ,Dain JG,Deems R,Fillers WS,Foley JE,Knorr DC,Nadelson J,Otero DA,Simpson R,Strohschein RJ,Young DA

更新日期：1999-01-14 00:00:00

abstract：:A series of 3-indoleacrylonitrile tyrphostins, 2-chloro-3-phenylquinolines, and 3-arylquinoxalines were prepared and tested for inhibition of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The potency of the inhibitors was found to be quinoxalines > quinolines > indoles. Lipophilic groups...

journal_title：Journal of medicinal chemistry

authors： Gazit A,App H,McMahon G,Chen J,Levitzki A,Bohmer FD

更新日期：1996-05-24 00:00:00

abstract：:Models for predicting oral drug absorption kinetics were developed by correlating absorption rate constants in humans (K(a)) with computational molecular descriptors. The K(a) values of a set of 22 passively absorbed drugs were derived from human plasma time-concentration profiles using a deconvolution approach. The K...

journal_title：Journal of medicinal chemistry

authors： Linnankoski J,Mäkelä JM,Ranta VP,Urtti A,Yliperttula M

更新日期：2006-06-15 00:00:00

abstract：:Analogues of the potent inhibitor of choline acetyltransferase (CAT) (E)-4-(1-naphthylvinyl)pyridine methiodide were synthesized and evaluated for their ability to inhibit CAT and protect against nerve agent intoxication. Several compounds, notably (E)-1-(2-hydroxyethyl)-(1-naphthylvinyl)pyridinium bromide (3), (E)-1-...

journal_title：Journal of medicinal chemistry

authors： Gray AP,Platz RD,Henderson TR,Chang TC,Takahashi K,Dretchen KL

更新日期：1988-04-01 00:00:00

abstract：:Extensive quantum chemical calculations have been made of the electronic distribution and conformational behavior of meperidine and desmethyl-, (+)-alpha, and (+)-beta-prodine using PCILO, a semiempirical molecular orbital method. For this series of opiates, a phenyl equatorial conformation was preferred over a phenyl...

journal_title：Journal of medicinal chemistry

authors： Loew GH,Jester JR

更新日期：1975-11-01 00:00:00

abstract：:Glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) are proglucagon derived peptides that are released from gut endocrine cells in response to nutrient intake. These molecules are rapidly inactivated by the action of dipeptidyl peptidase IV (DPP-4) which limits their use as therapeutic agents. The rece...

journal_title：Journal of medicinal chemistry

authors： Suzuki R,Brown GA,Christopher JA,Scully CCG,Congreve M

更新日期：2020-02-13 00:00:00

abstract：:Matrix metalloproteinases (MMPs) are a family of over 20 zinc-dependent enzymes that hydrolyze connective tissue and are involved in a variety of diseases, which are associated with undesired tissue breakdown. This paper reports the synthesis, characterization, and biological evaluation of a novel class of MMP inhibit...

journal_title：Journal of medicinal chemistry

authors： Breuer E,Salomon CJ,Katz Y,Chen W,Lu S,Röschenthaler GV,Hadar R,Reich R

更新日期：2004-05-20 00:00:00

abstract：:Quantitative structure-activity relationship studies have been performed on two types of sulfonamides with hypoglycemic activity. In the case of the 2-benzenesulfonamidopyrimidines, substituted in the 5 position of the pyrimidine ring a correlation between hydrophobic forces, expressed as Rm values, and the binding to...

journal_title：Journal of medicinal chemistry

authors： Seydel JK,Ahrens H,Losert W

更新日期：1975-03-01 00:00:00

abstract：:Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compo...

journal_title：Journal of medicinal chemistry

authors： Graham SL,Hoffman JM,Gautheron P,Michelson SR,Scholz TH,Schwam H,Shepard KL,Smith AM,Smith RL,Sondey JM

更新日期：1990-02-01 00:00:00

abstract：:Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle th...

journal_title：Journal of medicinal chemistry

authors： Chen L,Zhuang C,Lu J,Jiang Y,Sheng C

更新日期：2018-03-22 00:00:00

abstract：:Several 4-benzyl analogues of 5-ethyl-6-methyl-4-(phenylthio)pyridin-2(1H)-ones were synthesized and evaluated for their anti-HIV-l activities. Key transformations include metalation at the 4-C-position of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5) and its coupling with benzyl bromide or benzaldehyde deriv...

journal_title：Journal of medicinal chemistry

authors： Dollé V,Nguyen CH,Legraverend M,Aubertin AM,Kirn A,Andreola ML,Ventura M,Tarrago-Litvak L,Bisagni E

更新日期：2000-10-19 00:00:00

abstract：:Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient molecular interactions. This can help identify target proteins and map the ligand's interactome. Diazirine probes have even be...

journal_title：Journal of medicinal chemistry

authors： Hill JR,Robertson AAB

更新日期：2018-08-23 00:00:00