Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate.

abstract：:A series of 4(6)-(benzyloxy)-2,6(4)-diamino-5-(nitro or nitroso)pyrimidine derivatives and analogues of which 4(6)-benzyloxy groups were replaced with a (2-, 3-, or 4-fluorobenzyl)oxy or (2-, 3-, or 4-pyridylmethyl)oxy group, was synthesized. The abilities of these compounds to inhibit human O6-alkylguanine-DNA alkylt...

journal_title：Journal of medicinal chemistry

authors： Terashima I,Kohda K

更新日期：1998-02-12 00:00:00

abstract：:New ruthenium(II) and iron(II) organometallic compounds of general formula [(η(5)-C5H5)M(PP)Lc][PF6], bearing carbohydrate derivative ligands (Lc), were prepared and fully characterized and the crystal structures of five of those compounds were determined by X-ray diffraction studies. Cell viability of colon cancer HC...

journal_title：Journal of medicinal chemistry

authors： Florindo PR,Pereira DM,Borralho PM,Rodrigues CM,Piedade MF,Fernandes AC

更新日期：2015-05-28 00:00:00

abstract：:In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in...

journal_title：Journal of medicinal chemistry

authors： Rochais C,Lecoutey C,Gaven F,Giannoni P,Hamidouche K,Hedou D,Dubost E,Genest D,Yahiaoui S,Freret T,Bouet V,Dauphin F,Sopkova de Oliveira Santos J,Ballandonne C,Corvaisier S,Malzert-Fréon A,Legay R,Boulouard M,Claeysen

更新日期：2015-04-09 00:00:00

abstract：:Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC5...

journal_title：Journal of medicinal chemistry

authors： Liu J,Zheng S,Akerstrom VL,Yuan C,Ma Y,Zhong Q,Zhang C,Zhang Q,Guo S,Ma P,Skripnikova EV,Bratton MR,Pannuti A,Miele L,Wiese TE,Wang G

更新日期：2016-09-08 00:00:00

abstract：:We have found that (R,S)-1-(phenylthio)-aminopropane (4a), a synthetic alternate substrate for the terminal enzyme of norepinephrine biosynthesis, dopamine beta-monooxygenase (DBM), is both an indirect sympathomimetic and a potent antihypertensive agent in spontaneously hypertensive rats. We demonstrate herein that th...

journal_title：Journal of medicinal chemistry

authors： Herman HH,Husain PA,Colbert JE,Schweri MM,Pollock SH,Fowler LC,May SW

更新日期：1991-03-01 00:00:00

abstract：:N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both P...

journal_title：Journal of medicinal chemistry

authors： Rackham MD,Brannigan JA,Rangachari K,Meister S,Wilkinson AJ,Holder AA,Leatherbarrow RJ,Tate EW

更新日期：2014-03-27 00:00:00

abstract：:Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial ...

journal_title：Journal of medicinal chemistry

authors： Song Y,Connor DT,Sercel AD,Sorenson RJ,Doubleday R,Unangst PC,Roth BD,Beylin VG,Gilbertsen RB,Chan K,Schrier DJ,Guglietta A,Bornemeier DA,Dyer RD

更新日期：1999-04-08 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：:In 1869, Crum Brown discovered the first structure-activity link by showing that alkaloids, even convulsive ones, were converted by N-methylation to muscle relaxants resembling curarine (itself a quaternary amine). This led to an attempt to link every type of drug action to its own cluster of atoms. This quest was jol...

journal_title：Journal of medicinal chemistry

authors： Albert A

更新日期：1982-01-01 00:00:00

abstract：:A systematic investigation of the impact of spermidine analogues both in vitro and in vivo is described. The study characterizes the effects of these analogues on L1210 cell growth, polyamine pools, ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, spermidine/spermine N1-acetyltransferase, the maintenanc...

journal_title：Journal of medicinal chemistry

authors： Bergeron RJ,Feng Y,Weimar WR,McManis JS,Dimova H,Porter C,Raisler B,Phanstiel O

更新日期：1997-05-09 00:00:00

abstract：:Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and i...

journal_title：Journal of medicinal chemistry

authors： Giardinà D,Martarelli D,Sagratini G,Angeli P,Ballinari D,Gulini U,Melchiorre C,Poggesi E,Pompei P

更新日期：2009-08-13 00:00:00

abstract：:The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as w...

journal_title：Journal of medicinal chemistry

authors： Giraud F,Alves G,Debiton E,Nauton L,Théry V,Durieu E,Ferandin Y,Lozach O,Meijer L,Anizon F,Pereira E,Moreau P

更新日期：2011-07-14 00:00:00

abstract：:The sponge-derived polyketide macrolides fijianolides A (1) and B (2), isolaulimalide and laulimalide, have taxol-like microtubule-stabilizing activity, and the latter exhibits potent cytotoxicity. Insight on the biogeographical and phenotypic variations of Cacospongia mycofijiensis is presented that will enable a fut...

journal_title：Journal of medicinal chemistry

authors： Johnson TA,Tenney K,Cichewicz RH,Morinaka BI,White KN,Amagata T,Subramanian B,Media J,Mooberry SL,Valeriote FA,Crews P

更新日期：2007-08-09 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：:We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacolo...

journal_title：Journal of medicinal chemistry

authors： Kelly B,McMullan M,Muguruza C,Ortega JE,Meana JJ,Callado LF,Rozas I

更新日期：2015-01-22 00:00:00

abstract：:Novel analogues of the class III antiarrhythmic agent 1-[2-hydroxy-2-[4-[(methylsulfonyl)amino]phenyl]ethyl]-3-methyl-1H- imidazolium chloride, 1 (CK-1649), were prepared and investigated for their class III electrophysiological activity on isolated canine cardiac Purkinje fibers and ventricular muscle tissue. Structu...

journal_title：Journal of medicinal chemistry

authors： Lis R,Davey DD,Morgan TK Jr,Lumma WC Jr,Wohl RA,Jain VK,Wan CN,Argentieri TM,Sullivan ME,Cantor EH

更新日期：1987-12-01 00:00:00

abstract：:Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally rela...

journal_title：Journal of medicinal chemistry

authors： Cherblanc FL,Chapman KL,Reid J,Borg AJ,Sundriyal S,Alcazar-Fuoli L,Bignell E,Demetriades M,Schofield CJ,DiMaggio PA Jr,Brown R,Fuchter MJ

更新日期：2013-11-14 00:00:00

abstract：:The alcohol-abuse deterrent disulfiram (DSF) is shown to have a highly selective toxicity against melanoma in culture, inducing a largely apoptotic response, with much lower toxicity against several other cell lines. Melanoma cell lines derived from different stages (radial, vertical, and metastatic phase) were all se...

journal_title：Journal of medicinal chemistry

authors： Cen D,Brayton D,Shahandeh B,Meyskens FL Jr,Farmer PJ

更新日期：2004-12-30 00:00:00

abstract：:Novel lavendamycins including two water soluble derivatives were synthesized via short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptophans produced lavendamycin esters or amides 11-17. Lavendamycins 18-21 were obtained, respectively, by further transformat...

journal_title：Journal of medicinal chemistry

authors： Behforouz M,Cai W,Stocksdale MG,Lucas JS,Jung JY,Briere D,Wang A,Katen KS,Behforouz NC

更新日期：2003-12-18 00:00:00

abstract：:Benzimidazole-N-oxide modifications of potent lipophilic dihydrofolate reductase (DHFR) inhibitors (e.g., methylbenzoprim 1 and dichlorobenzoprim 2) have been prepared by base-promoted cyclization of the nitrophenylbenzylamino groups to explore the possibility that abrogation of DHFR-inhibitory activity might reveal c...

journal_title：Journal of medicinal chemistry

authors： Richardson ML,Croughton KA,Matthews CS,Stevens MF

更新日期：2004-07-29 00:00:00

abstract：:In colorectal cancer, adenomatous polyposis coli (APC) interacts with Rho guanine-nucleotide-exchange factor 4 (Asef), thereby stimulating aberrant colorectal-cancer-cell migration. Consequently, the APC-Asef interaction represents a promising therapeutic target for mitigating colorectal-cancer migration. In this stud...

journal_title：Journal of medicinal chemistry

authors： Yang X,Zhong J,Zhang Q,Qian J,Song K,Ruan C,Xu J,Ding K,Zhang J

更新日期：2018-09-13 00:00:00

abstract：:A new series of compounds were designed as structural analogues of the alpha(1)-AR ligand RN5 (4), characterized by a tricyclic 5H-pyrimido[5,4-b]indole-(1H,3H)2,4-dione system connected through an alkyl chain to a phenylpiperazine (PP) moiety. These compounds were synthesized and tested in binding assays on human alp...

journal_title：Journal of medicinal chemistry

authors： Romeo G,Materia L,Manetti F,Cagnotto A,Mennini T,Nicoletti F,Botta M,Russo F,Minneman KP

更新日期：2003-07-03 00:00:00

abstract：:Both HIV-EP1 (also called PRDII-BF1 or MBP-1), a zinc finger protein, and NF-kappa B, a Rel family protein, bind to kappa B site present in the enhancer of multiple cellular and viral genes involved in immune function and inflammatory response including HIV-1 LTR and human interferon beta gene. When cells are exposed ...

journal_title：Journal of medicinal chemistry

authors： Otsuka M,Fujita M,Aoki T,Ishii S,Sugiura Y,Yamamoto T,Inoue J

更新日期：1995-08-18 00:00:00

abstract：:The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to...

journal_title：Journal of medicinal chemistry

authors： McKew JC,Lee KL,Shen MW,Thakker P,Foley MA,Behnke ML,Hu B,Sum FW,Tam S,Hu Y,Chen L,Kirincich SJ,Michalak R,Thomason J,Ipek M,Wu K,Wooder L,Ramarao MK,Murphy EA,Goodwin DG,Albert L,Xu X,Donahue F,Ku MS,Keit

更新日期：2008-06-26 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：:A series of 3-fluoromethyl-1,2,3,4-tetrahydroisoquinolines (3-fluoromethyl-THIQs) was proposed, and their phenylethanolamine N-methyltransferase (PNMT) and alpha(2)-adrenoceptor affinities were predicted through the use of comparative molecular field analysis (CoMFA) models. These compounds were synthesized and evalua...

journal_title：Journal of medicinal chemistry

authors： Grunewald GL,Caldwell TM,Li Q,Slavica M,Criscione KR,Borchardt RT,Wang W

更新日期：1999-09-09 00:00:00

abstract：:A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in ...

journal_title：Journal of medicinal chemistry

authors： Bock MG,DiPardo RM,Evans BE,Rittle KE,Whitter WL,Garsky VM,Gilbert KF,Leighton JL,Carson KL,Mellin EC

更新日期：1993-12-24 00:00:00

abstract：:In a previous paper, we reported the N-hydroxyformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Despite its attraction as a potential therapeutic agent for cerebral diseases, the preparation of an injectable formulation of HET0016 was limited by its poor solubility under neutral cond...

journal_title：Journal of medicinal chemistry

authors： Nakamura T,Sato M,Kakinuma H,Miyata N,Taniguchi K,Bando K,Koda A,Kameo K

更新日期：2003-12-04 00:00:00

abstract：:We synthesized two series (7a-i and 8a-i) of 2,3,5-substituted [1,2,4]-thiadiazole analogues of SCH-202676 (7a, 2,3-diphenyl-5-N-methylimino-2H-[1,2,4]-thiadiazole) with emphasis on the N-imino substituent. Compounds 7a-g,i and 8a-g at a final concentration of 1 microM significantly inhibited [(3)H]CCPA (2-chloro-N(6)...

journal_title：Journal of medicinal chemistry

authors： Göblyös A,de Vries H,Brussee J,Ijzerman AP

更新日期：2005-02-24 00:00:00

abstract：:The effect of structural change on the biological activity of a series of imidazothiazoles and thiazolobenzimidazoles is described. It was found that compounds with polar substituents at the 2 or 3 position of the ring system are less acutely toxic while maintaining antiinflammatory activity. Other structural changes,...

journal_title：Journal of medicinal chemistry

authors： Powers LJ,Fogt SW,Ariyan ZS,Rippin DJ,Heilman RD,Matthews RJ

更新日期：1981-05-01 00:00:00