Improved delivery through biological membranes. 1. Synthesis and properties of 1-methyl-1,6-dihydropyridine-2-carbaldoxime, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride.

abstract：:A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H 3 receptor inverse agonists. 2-Methyl-3-(4-[[3-(1-pyrrolidinyl)propyl]oxy]phenyl)-5-(trifluoromethyl)-4(3 H)-quinazolinone ( 1) was identified as a promising derivative for further evaluation following optimization of key paramet...

journal_title：Journal of medicinal chemistry

authors： Nagase T,Mizutani T,Ishikawa S,Sekino E,Sasaki T,Fujimura T,Ito S,Mitobe Y,Miyamoto Y,Yoshimoto R,Tanaka T,Ishihara A,Takenaga N,Tokita S,Fukami T,Sato N

更新日期：2008-08-14 00:00:00

abstract：:Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially use...

journal_title：Journal of medicinal chemistry

authors： Henderson JL,Kormos BL,Hayward MM,Coffman KJ,Jasti J,Kurumbail RG,Wager TT,Verhoest PR,Noell GS,Chen Y,Needle E,Berger Z,Steyn SJ,Houle C,Hirst WD,Galatsis P

更新日期：2015-01-08 00:00:00

abstract：:A series of biphenyl analogues of the new tuberculosis drug PA-824 was prepared, primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side...

journal_title：Journal of medicinal chemistry

authors： Palmer BD,Thompson AM,Sutherland HS,Blaser A,Kmentova I,Franzblau SG,Wan B,Wang Y,Ma Z,Denny WA

更新日期：2010-01-14 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：:3-O-tert-Butylmorphine (5) was prepared from 6-O-acetylmorphine (3) via alkylation with N,N-dimethylformamide di-tert-butyl acetal, followed by hydrolytic removal of the 3-(dimethylamino)-2-propenoate group. The same process was used to prepare the tert-butyl ether of levorphanol (6), (-)-3-tert-butoxy-N-methylmorphin...

journal_title：Journal of medicinal chemistry

authors： Mohacsi E,Leimgruber W,Baruth H

更新日期：1982-10-01 00:00:00

abstract：:A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antib...

journal_title：Journal of medicinal chemistry

authors： Wentland MP,Bailey DM,Cornett JB,Dobson RA,Powles RG,Wagner RB

更新日期：1984-09-01 00:00:00

abstract：:The synthetic pentasaccharide (1) corresponding to the heparin sequence which binds to, and activates, antithrombin III (AT III) is a potent antithrombotic compound in several animal models of venous thrombosis. We describe here the preparation and the pharmacological properties of 34, an analogue of oligosaccharide 1...

journal_title：Journal of medicinal chemistry

authors： Petitou M,Duchaussoy P,Jaurand G,Gourvenec F,Lederman I,Strassel JM,Bârzu T,Crépon B,Hérault JP,Lormeau JC,Bernat A,Herbert JM

更新日期：1997-05-23 00:00:00

abstract：:A series of N-substituted 3-aminoglutarimides have been synthesized and tested for inhibitory activity against a range of chemokines in vitro and for suppression of lipopolysaccharide-induced inflammation in vivo. The results show that they represent the first class of small molecules with broad-spectrum chemokine inh...

journal_title：Journal of medicinal chemistry

authors： Fox DJ,Reckless J,Warren SG,Grainger DJ

更新日期：2002-01-17 00:00:00

abstract：:We explore the significance of pi-cation interactions in the binding of ligands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the interaction of aromatic amino acid side chains with the cation-containing heterocyclic ring fragmen...

journal_title：Journal of medicinal chemistry

authors： Schmitt JD,Sharples CG,Caldwell WS

更新日期：1999-08-12 00:00:00

abstract：:The natural abundance 13C magnetic resonance spectra of a series of sulfonamide drugs(sulfanilamide, sulfaguanidine,sulfathiazole, sulfasuxidine, sulfadiazine, sulfamerazine, sulfamethiazine, and sulfapyridine) have been determined at 25.15 MHz employing the pulse Fourier transform technique. The chemical shefts have ...

journal_title：Journal of medicinal chemistry

authors： Chang C,Floss HG,Peck GE

更新日期：1975-05-01 00:00:00

abstract：:The definitive diagnosis of Alzheimer's disease (AD) requires the detection of amyloid plaques in postmortem brain. Although the amount of fibrillar amyloid roughly correlates with the severity of symptoms at the time of death, the temporal relationship between amyloid deposition, neuronal loss, and cognitive decline ...

journal_title：Journal of medicinal chemistry

authors： Zhen W,Han H,Anguiano M,Lemere CA,Cho CG,Lansbury PT Jr

更新日期：1999-07-29 00:00:00

abstract：:We describe a new method, Compass, for predicting the biological activities of molecules based on the activities and three-dimensional structures of other molecules. The method improves on previous techniques by representing only the surface of molecules, by incorporating a nonlinear statistical method, and by automat...

journal_title：Journal of medicinal chemistry

authors： Jain AN,Koile K,Chapman D

更新日期：1994-07-22 00:00:00

abstract：:Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket ...

journal_title：Journal of medicinal chemistry

authors： Kettle JG,Bagal SK,Bickerton S,Bodnarchuk MS,Breed J,Carbajo RJ,Cassar DJ,Chakraborty A,Cosulich S,Cumming I,Davies M,Eatherton A,Evans L,Feron L,Fillery S,Gleave ES,Goldberg FW,Harlfinger S,Hanson L,Howard M,Howe

更新日期：2020-05-14 00:00:00

abstract：:A series of 2'- and 3'-fluorinated 2',3'-dideoxynucleosides and 3'-azido-2',3'-dideoxynucleosides were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus-1 (HIV-1) replication in MT-4 cells. Neither conversion of 3'-fluoro- or 3'-azido-2',3'-dideoxyadenosine to the correspondi...

journal_title：Journal of medicinal chemistry

authors： Van Aerschot A,Herdewijn P,Balzarini J,Pauwels R,De Clercq E

更新日期：1989-08-01 00:00:00

abstract：:Four highly charged, water soluble platinum-acridine bisintercalating agents have been synthesized. Depending on the cis/trans isomerism of the metal and the nature of the acridine side chains, bisintercalation induces/stabilizes the classical Watson-Crick B-form or a non-B-form. Circular dichroism spectra and chemica...

journal_title：Journal of medicinal chemistry

authors： Choudhury JR,Guddneppanavar R,Saluta G,Kucera GL,Bierbach U

更新日期：2008-06-12 00:00:00

abstract：:We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer's disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca(2+) channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatase...

journal_title：Journal of medicinal chemistry

authors： Lajarín-Cuesta R,Nanclares C,Arranz-Tagarro JA,González-Lafuente L,Arribas RL,Araujo de Brito M,Gandía L,de Los Ríos C

更新日期：2016-07-14 00:00:00

abstract：:Notch is a membrane inserted protein activated by the membrane-inserted γ-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we h...

journal_title：Journal of medicinal chemistry

authors： Juillerat-Jeanneret L,Flohr A,Schneider M,Walter I,Wyss JC,Kumar R,Golshayan D,Aebi JD

更新日期：2015-10-22 00:00:00

abstract：:A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl s...

journal_title：Journal of medicinal chemistry

authors： Devine SM,Yong C,Amenuvegbe D,Aurelio L,Muthiah D,Pouton C,Callaghan R,Capuano B,Scammells PJ

更新日期：2018-09-27 00:00:00

abstract：:N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations w...

journal_title：Journal of medicinal chemistry

authors： Carroll FI,Chaudhari S,Thomas JB,Mascarella SW,Gigstad KM,Deschamps J,Navarro HA

更新日期：2005-12-29 00:00:00

abstract：:New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2...

journal_title：Journal of medicinal chemistry

authors： Monge A,Peña MC,Palop JA,Calderó JM,Roca J,García E,Romero G,del Río J,Lasheras B

更新日期：1994-04-29 00:00:00

abstract：:The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse agonism to agonism, indica...

journal_title：Journal of medicinal chemistry

authors： Els S,Schild E,Petersen PS,Kilian TM,Mokrosinski J,Frimurer TM,Chollet C,Schwartz TW,Holst B,Beck-Sickinger AG

更新日期：2012-09-13 00:00:00

abstract：:As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, in...

journal_title：Journal of medicinal chemistry

authors： Kong X,Pan P,Sun H,Xia H,Wang X,Li Y,Hou T

更新日期：2019-12-26 00:00:00

abstract：:A series of 4- aminobenzamides of some simple primary and secondary amines were prepared and evaluated for anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and pentylenetetrazole ( metrazole ) and in the rotorod assay for neurologic deficit. For those N-alkyl amides te...

journal_title：Journal of medicinal chemistry

authors： Clark CR,Wells MJ,Sansom RT,Norris GN,Dockens RC,Ravis WR

更新日期：1984-06-01 00:00:00

abstract：:Several optically active N-(indol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. IC50 values were measured and revealed that the D form of the amino acid moiety of the compounds was more potent than both the L form and racemic form,...

journal_title：Journal of medicinal chemistry

authors： Primofiore G,Marini AM,Da Settimo F,Martini C,Bardellini A,Giannaccini G,Lucacchini A

更新日期：1989-12-01 00:00:00

abstract：:A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based sub...

journal_title：Journal of medicinal chemistry

authors： Turner SR,Strohbach JW,Tommasi RA,Aristoff PA,Johnson PD,Skulnick HI,Dolak LA,Seest EP,Tomich PK,Bohanon MJ,Horng MM,Lynn JC,Chong KT,Hinshaw RR,Watenpaugh KD,Janakiraman MN,Thaisrivongs S

更新日期：1998-08-27 00:00:00

abstract：:Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5...

journal_title：Journal of medicinal chemistry

authors： Krecmerová M,Holý A,Pohl R,Masojídková M,Andrei G,Naesens L,Neyts J,Balzarini J,De Clercq E,Snoeck R

更新日期：2007-11-15 00:00:00

abstract：:Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code ) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide i...

journal_title：Journal of medicinal chemistry

authors： Greenidge PA,Mérette SA,Beck R,Dodson G,Goodwin CA,Scully MF,Spencer J,Weiser J,Deadman JJ

更新日期：2003-04-10 00:00:00

abstract：:To provide practical means for rapidly scanning the extensive experimental combinatorial chemistry libraries now available for high-throughput screening (HTS), it is essential to establish computational virtual ligand screening (VLS) techniques to rapidly identify out of a large library all active compounds against a ...

journal_title：Journal of medicinal chemistry

authors： Floriano WB,Vaidehi N,Zamanakos G,Goddard WA 3rd

更新日期：2004-01-01 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：:It is presently known that the long-term failure in the treatment of AIDS with the currently available nucleotide reverse transcriptase inhibitors (NRTIs) is related to the development of resistance by reverse transcriptase (RT) at the binding or incorporation level or both, or subsequent to the nucleotide incorporati...

journal_title：Journal of medicinal chemistry

authors： Carvalho AT,Fernandes PA,Ramos MJ

更新日期：2006-12-28 00:00:00