Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity.

abstract：:Certain derivatives containing the 1,2-dihydropyrido[3,4-b]pyrazine (1-deaza-7,8-dihydropteridine) ring system are active against experimental neoplasms in mice. The mechanism of action of these agents has been attributed to the accumulation of cells at mitosis. Identification of the structural features that are neces...

journal_title：Journal of medicinal chemistry

authors： Temple C Jr,Wheeler GP,Elliott RD,Rose JD,Comber RN,Montgomery JA

更新日期：1983-01-01 00:00:00

abstract：:The variation in amino acid sequence within sets of peptides is described by three principal properties, z1, z2, and z3, per varied amino acid position. These principal properties are derived from a principal components analysis of a matrix of 29 physicochemical variables for the 20 coded (in mRNA) amino acids. The sc...

journal_title：Journal of medicinal chemistry

authors： Hellberg S,Sjöström M,Skagerberg B,Wold S

更新日期：1987-07-01 00:00:00

abstract：:Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct se...

journal_title：Journal of medicinal chemistry

authors： Ehrt C,Brinkjost T,Koch O

更新日期：2016-05-12 00:00:00

abstract：:We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rati...

journal_title：Journal of medicinal chemistry

authors： Poutiainen PK,Oravilahti T,Peräkylä M,Palvimo JJ,Ihalainen JA,Laatikainen R,Pulkkinen JT

更新日期：2012-07-26 00:00:00

abstract：:Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bio...

journal_title：Journal of medicinal chemistry

authors： Bolós J,Gubert S,Anglada L,Planas JM,Burgarolas C,Castelló JM,Sacristán A,Ortiz JA

更新日期：1996-07-19 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：:Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-...

journal_title：Journal of medicinal chemistry

authors： Hoekstra WJ,Maryanoff BE,Damiano BP,Andrade-Gordon P,Cohen JH,Costanzo MJ,Haertlein BJ,Hecker LR,Hulshizer BL,Kauffman JA,Keane P,McComsey DF,Mitchell JA,Scott L,Shah RD,Yabut SC

更新日期：1999-12-16 00:00:00

abstract：:Three analogs of luteinizing hormone-releasing hormone (LH-RH) of the structure less than Glu-His-Trp-Ser-Tyr-Gly-Gly-Leu-Arg-Pro-Gly-NH2, involving substitutions inpositions 1, 3, and 8 with nonprotein amino acids, have been synthesized by the solid-phase method. They are [pyro-L-alpha-(1-aminoadipic)]-LH-RH, [3-(2-n...

journal_title：Journal of medicinal chemistry

authors： Prasad KU,Roeske RW,Weitl FL,Vilchez-Martinez JA,Schally AV

更新日期：1976-04-01 00:00:00

abstract：:From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors ...

journal_title：Journal of medicinal chemistry

authors： Llinàs-Brunet M,Bailey MD,Bolger G,Brochu C,Faucher AM,Ferland JM,Garneau M,Ghiro E,Gorys V,Grand-Maître C,Halmos T,Lapeyre-Paquette N,Liard F,Poirier M,Rhéaume M,Tsantrizos YS,Lamarre D

更新日期：2004-03-25 00:00:00

abstract：:A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a b...

journal_title：Journal of medicinal chemistry

authors： Konkel MJ,Lagu B,Boteju LW,Jimenez H,Noble S,Walker MW,Chandrasena G,Blackburn TP,Nikam SS,Wright JL,Kornberg BE,Gregory T,Pugsley TA,Akunne H,Zoski K,Wise LD

更新日期：2006-06-29 00:00:00

abstract：:Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with a nonsubstrate analog inhibitor. Given the active site simil...

journal_title：Journal of medicinal chemistry

authors： Luciani R,Saxena P,Surade S,Santucci M,Venturelli A,Borsari C,Marverti G,Ponterini G,Ferrari S,Blundell TL,Costi MP

更新日期：2016-10-13 00:00:00

abstract：:A gadolinium complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and benzothiazole-aniline (BTA) of the type [Gd(DO3A-BTA)(H2O)] has been prepared for use as a single molecule theranostic agent. The kinetic inertness and r1 relaxivity (= 3.84 mM(-1) s(-1)) of the complex compare well with those of s...

journal_title：Journal of medicinal chemistry

authors： Kim HK,Kang MK,Jung KH,Kang SH,Kim YH,Jung JC,Lee GH,Chang Y,Kim TJ

更新日期：2013-10-24 00:00:00

abstract：:A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared ...

journal_title：Journal of medicinal chemistry

authors： Yang LX,Huang KX,Li HB,Gong JX,Wang F,Feng YB,Tao QF,Wu YH,Li XK,Wu XM,Zeng S,Spencer S,Zhao Y,Qu J

更新日期：2009-12-10 00:00:00

abstract：:A series of (8 beta)-6-methylergoline amide derivatives was synthesized with various alkyl substituents in the N1-position in order to evaluate their effectiveness in blocking vascular 5HT2 receptors. The influence of both the N1 substituent and amide derivative proved to be of great importance on binding affinities t...

journal_title：Journal of medicinal chemistry

authors： Misner JW,Garbrecht WL,Marzoni G,Whitten KR,Cohen ML

更新日期：1990-02-01 00:00:00

abstract：:We have synthesized a set of bis-pyranobenzoquinones through a direct and highly efficient approach based on a double intramolecular domino Knoevenagel hetero Diels-Alder reaction. These bis-pyranobenzoquinone derivatives are compounds whose skeletons have similarities to those of some anticancerous and leishmanicidal...

journal_title：Journal of medicinal chemistry

authors： Jiménez-Alonso S,Pérez-Lomas AL,Estévez-Braun A,Muñoz Martinez F,Chávez Orellana H,Ravelo AG,Gamarro F,Castanys S,López M

更新日期：2008-11-27 00:00:00

abstract：:125I-labeled (E)-18-iodo-17-octadecenoic acid (13) has been prepared and evaluated in rats to determine the myocardial uptake and retention and degree of in vivo deiodination of this model iodovinyl-substituted fatty acid, which contains no structural perturbation to inhibit metabolism. This new agent was prepared by ...

journal_title：Journal of medicinal chemistry

authors： Knapp FF Jr,Goodman MM,Kabalka GW,Sastry KA

更新日期：1984-01-01 00:00:00

abstract：:The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and ox...

journal_title：Journal of medicinal chemistry

authors： Heier RF,Dolak LA,Duncan JN,Hyslop DK,Lipton MF,Martin IJ,Mauragis MA,Piercey MF,Nichols NF,Schreur PJ,Smith MW,Moon MW

更新日期：1997-02-28 00:00:00

abstract：:The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamin...

journal_title：Journal of medicinal chemistry

authors： Rose NR,Woon EC,Tumber A,Walport LJ,Chowdhury R,Li XS,King ON,Lejeune C,Ng SS,Krojer T,Chan MC,Rydzik AM,Hopkinson RJ,Che KH,Daniel M,Strain-Damerell C,Gileadi C,Kochan G,Leung IK,Dunford J,Yeoh KK,Ratcliffe PJ

更新日期：2012-07-26 00:00:00

abstract：:The chemokine receptor CXCR4 is a critical regulator of inflammation and immune surveillance, and it is specifically implicated in cancer metastasis and HIV-1 infection. On the basis of the observation that several of the known antagonists remarkably share a C(2) symmetry element, we constructed symmetric dimers with ...

journal_title：Journal of medicinal chemistry

authors： Demmer O,Dijkgraaf I,Schumacher U,Marinelli L,Cosconati S,Gourni E,Wester HJ,Kessler H

更新日期：2011-11-10 00:00:00

abstract：:The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening of MGL inhibitor...

journal_title：Journal of medicinal chemistry

authors： Saario SM,Poso A,Juvonen RO,Järvinen T,Salo-Ahen OM

更新日期：2006-07-27 00:00:00

abstract：:Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated ...

journal_title：Journal of medicinal chemistry

authors： Lainchbury M,Matthews TP,McHardy T,Boxall KJ,Walton MI,Eve PD,Hayes A,Valenti MR,de Haven Brandon AK,Box G,Aherne GW,Reader JC,Raynaud FI,Eccles SA,Garrett MD,Collins I

更新日期：2012-11-26 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：:To study the influence of substitution of CN for C identical to CH in the anti-herpes virus nucleoside 5-(propynyloxy)-2'-deoxyuridine (1), 5-[(cyanomethylene)oxy]-2'-deoxyuridine (2) was prepared. When the potassium salt of 5-hydroxy-2'-deoxyuridine was reacted with iodoacetonitrile in dry DMF, the bisalkylated produ...

journal_title：Journal of medicinal chemistry

authors： Huang GF,Okada M,De Clercq E,Torrence PF

更新日期：1981-04-01 00:00:00

abstract：:Targeted imaging requires contrast agents that remain in the vasculature for extended periods of time. A new contrast agent is described in which gadolinium is encapsulated within an extremely stable carbon sphere, thus allowing for safe extended residence. Water solubility and small particle size is achieved with nov...

journal_title：Journal of medicinal chemistry

authors： MacFarland DK,Walker KL,Lenk RP,Wilson SR,Kumar K,Kepley CL,Garbow JR

更新日期：2008-07-10 00:00:00

abstract：:Tyrosine kinases often play pivotal roles in the pathogenesis of cancer and are good candidates for therapeutic intervention and targeted molecular imaging. The precursor synthesis, radiosynthesis, and biological characterization of a fluorine-18 analog of dasatinib, a multitargeted kinase inhibitor, are reported. Com...

journal_title：Journal of medicinal chemistry

authors： Veach DR,Namavari M,Pillarsetty N,Santos EB,Beresten-Kochetkov T,Lambek C,Punzalan BJ,Antczak C,Smith-Jones PM,Djaballah H,Clarkson B,Larson SM

更新日期：2007-11-15 00:00:00

abstract：:Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacoki...

journal_title：Journal of medicinal chemistry

authors： Brady SF,Stauffer KJ,Lumma WC,Smith GM,Ramjit HG,Lewis SD,Lucas BJ,Gardell SJ,Lyle EA,Appleby SD,Cook JJ,Holahan MA,Stranieri MT,Lynch JJ Jr,Lin JH,Chen IW,Vastag K,Naylor-Olsen AM,Vacca JP

更新日期：1998-01-29 00:00:00

abstract：:Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dih...

journal_title：Journal of medicinal chemistry

authors： Magedov IV,Frolova L,Manpadi M,Bhoga Ud,Tang H,Evdokimov NM,George O,Georgiou KH,Renner S,Getlik M,Kinnibrugh TL,Fernandes MA,Van slambrouck S,Steelant WF,Shuster CB,Rogelj S,van Otterlo WA,Kornienko A

更新日期：2011-06-23 00:00:00

abstract：:Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore i...

journal_title：Journal of medicinal chemistry

authors： Van der Poorten O,Knuhtsen A,Sejer Pedersen D,Ballet S,Tourwé D

更新日期：2016-12-22 00:00:00

abstract：:The preparation, determination of isomeric configuration, and antifungal properties of (E)-1-(5-chlorothien-2-yl)-2-(1H-imidazol-1-yl)ethanone 2,6-dichlorophenylhydrazone hydrochloride (1) are described. In vitro, compound 1 has been shown to have activity against Candida albicans comparable with miconazole. When admi...

journal_title：Journal of medicinal chemistry

authors： Dyer RL,Ellames GJ,Hamill BJ,Manley PW,Pope AM

更新日期：1983-03-01 00:00:00

abstract：:The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glio...

journal_title：Journal of medicinal chemistry

authors： Rais R,Jančařík A,Tenora L,Nedelcovych M,Alt J,Englert J,Rojas C,Le A,Elgogary A,Tan J,Monincová L,Pate K,Adams R,Ferraris D,Powell J,Majer P,Slusher BS

更新日期：2016-09-22 00:00:00