当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Imidazolopiperazines: lead optimization of the second-generation antimalarial agents.

Imidazolopiperazines: lead optimization of the second-generation antimalarial agents.

Abstract：

:On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Nagle A,Wu T,Kuhen K,Gagaring K,Borboa R,Francek C,Chen Z,Plouffe D,Lin X,Caldwell C,Ek J,Skolnik S,Liu F,Wang J,Chang J,Li C,Liu B,Hollenbeck T,Tuntland T,Isbell J,Chuan T,Alper PB,Fischli C,Brun R,Lakshm

doi

10.1021/jm300041e

subject

Has Abstract

pub_date

2012-05-10 00:00:00

pages

4244-73

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Structure-activity relationships of imidazo[4,5-f]quinoline partial structures and analogs. Discovery of pyrazolo[3,4-f]quinoline derivatives as potent immunostimulants.

    abstract：:Structure-activity studies have been carried out on a series of imidazo[4,5-f]quinoline derivatives reported to have potent in vivo immunostimulatory activity. This activity has been confirmed, and subtle structure-activity relationships have been uncovered which resulted in the identification of novel analogs (pyrazo...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00102a013

    authors： Moyer MP,Weber FH,Gross JL

    更新日期：1992-11-27 00:00:00

  • Structure-activity relationships and cancer-cell selective toxicity of novel inhibitors of glioma-associated oncogene homologue 1 (Gli1) mediated transcription.

    abstract：:We report novel inhibitors of Gli1-mediated transcription as potential anticancer agents. Focused chemical libraries were designed and assessed for inhibition of functional cell-based Gli1-mediated transcription and selective toxicity toward cancer cells. The SAR was revealed, and the selectivity of the lead compounds...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900106f

    authors： Mahindroo N,Connelly MC,Punchihewa C,Kimura H,Smeltzer MP,Wu S,Fujii N

    更新日期：2009-07-23 00:00:00

  • Anticonvulsant activity of some 4-aminobenzamides.

    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

    pub_type： 杂志文章

    doi：10.1021/jm00372a013

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

    更新日期：1984-06-01 00:00:00

  • In Vitro Antiviral Activity of New Oxazoline Derivatives as Potent Poliovirus Inhibitors.

    abstract：:The final stages of polio eradication are proving more difficult than the early phases, and the development of effective drugs and treatments is considered a priority; thus, the research is ongoing. A screening of our in-house chemical library against poliovirus Sabin strains led to the identification of compounds 5 a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01482

    authors： Madia VN,Messore A,Pescatori L,Saccoliti F,Tudino V,De Leo A,Scipione L,Fiore L,Rhoden E,Manetti F,Oberste MS,Di Santo R,Costi R

    更新日期：2019-01-24 00:00:00

  • Structure-function studies in a series of carboxyl-terminal octapeptide analogues of anaphylatoxin C5a.

    abstract：:The synthesis and structure-activity relationships of C-terminal octapeptide analogues of anaphylatoxin C5a have been studied. The introduction of hydrophobic amino acids into the N-acetylated native octapeptide (N-Ac-His-Lys-Asp-Met-Gln-Leu-Gly-Arg-OH) (1) has led to an analogue with 100 times more activity than the ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00080a004

    authors： Kawai M,Quincy DA,Lane B,Mollison KW,Or YS,Luly JR,Carter GW

    更新日期：1992-01-24 00:00:00

  • Synthesis and antiprotozoal properties of pentamidine congeners bearing the benzofuran motif.

    abstract：:Forty-eight cationically substituted pentamidine congeners possessing benzofuran rings were synthesized by a copper mediated heteroannulation of substituted o-iodophenols with phenyl acetylenes. Activities of compounds 1-48 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cyto...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9006406

    authors： Bakunov SA,Bakunova SM,Bridges AS,Wenzler T,Barszcz T,Werbovetz KA,Brun R,Tidwell RR

    更新日期：2009-09-24 00:00:00

  • Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives.

    abstract：:Tumor suppressor protein, p53, is an intracellular protein that is critical within the biochemical cascade that leads to cell death via apoptosis. Recent studies identified the tetrahydrobenzothiazole analogue, pifithrin-alpha (2), as a p53 inhibitor that was effective in protecting neuronal cells against a variety of...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm020044d

    authors： Zhu X,Yu QS,Cutler RG,Culmsee CW,Holloway HW,Lahiri DK,Mattson MP,Greig NH

    更新日期：2002-11-07 00:00:00

  • Exploiting the 4-Phenylquinazoline Scaffold for the Development of High Affinity Fluorescent Probes for the Translocator Protein (TSPO).

    abstract：:The quinazoline class was exploited to search for a new translocator protein (TSPO) fluorescent probe endowed with improved affinity and residence time (RT). Computational studies on an "in-house" collection of quinazoline derivatives, featuring highly steric demanding groups at the amide nitrogen, suggested that, des...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b01031

    authors： Milite C,Barresi E,Da Pozzo E,Costa B,Viviano M,Porta A,Messere A,Sbardella G,Da Settimo F,Novellino E,Cosconati S,Castellano S,Taliani S,Martini C

    更新日期：2017-09-28 00:00:00

  • Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A.

    abstract：:A series of balanol analogs in which the perhydroazepine ring and the p-hydroxybenzamide moiety were combined into an acyclic linked unit have been prepared and evaluated for their inhibitory properties against the serine/threonine kinase PKC. Several low-micromolar to low-nanomolar inhibitors of the alpha, beta I, be...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm960581w

    authors： Defauw JM,Murphy MM,Jagdmann GE Jr,Hu H,Lampe JW,Hollinshead SP,Mitchell TJ,Crane HM,Heerding JM,Mendoza JS,Davis JE,Darges JW,Hubbard FR,Hall SE

    更新日期：1996-12-20 00:00:00

  • Synthesis and hypoglycemic activity of phenacyltriphenylphosphoranes and phosphonium salts.

    abstract：:Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00243a021

    authors： Blank B,DiTullio NW,Deviney L,Roberts JT,Saunders HL

    更新日期：1975-09-01 00:00:00

  • Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule.

    abstract：:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00324

    authors： Cheng X,Merz KH,Vatter S,Zeller J,Muehlbeyer S,Thommet A,Christ J,Wölfl S,Eisenbrand G

    更新日期：2017-06-22 00:00:00

  • Toward selective ERbeta agonists for central nervous system disorders: synthesis and characterization of aryl benzthiophenes.

    abstract：:In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these com...

    journal_title：Journal of medicinal chemistry

    pub_type： 信件

    doi：10.1021/jm015577l

    authors： Schopfer U,Schoeffter P,Bischoff SF,Nozulak J,Feuerbach D,Floersheim P

    更新日期：2002-03-28 00:00:00

  • Dimeric 1,3-phenylene-bis(piperazinyl benzimidazole)s: synthesis and structure-activity investigations on their binding with human telomeric G-quadruplex DNA and telomerase inhibition properties.

    abstract：:Ligand-induced stabilization of G-quadruplex structures formed by the human telomeric DNA is an active area of research. The compounds which stabilize the G-quadruplexes often lead to telomerase inhibition. Herein we present the results of interaction of new monomeric and dimeric ligands having 1,3-phenylene-bis(piper...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200860b

    authors： Jain AK,Paul A,Maji B,Muniyappa K,Bhattacharya S

    更新日期：2012-04-12 00:00:00

  • Prospective identification of biologically active structures by topomer shape similarity searching.

    abstract：:The principle of bioisosterism-similarly shaped molecules are more likely to share biological properties than are other molecules-has long helped to guide drug discovery. An algorithmic implementation of this principle, based on shape comparisons of a single rule-generated "topomer" conformation per molecule, had been...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm990159q

    authors： Cramer RD,Poss MA,Hermsmeier MA,Caulfield TJ,Kowala MC,Valentine MT

    更新日期：1999-09-23 00:00:00

  • Gramine Derivatives Targeting Ca(2+) Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases.

    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

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00478

    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

  • Vinyl ethers of choline and congeners.

    abstract：:The vinyl ethers of choline and of its alpha- and beta-methyl homologues were prepared to determine their cholinergic effects and to determine whether a separation of the dual physiologic activity (nicotinic and muscarinic) reported for the vinyl ether of choline could be achieved by this modification. A literature me...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00229a015

    authors： Cannon JG,Gangjee A

    更新日期：1976-07-01 00:00:00

  • Toward development of targeted nonsteroidal antiandrogen-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-gadolinium complex for prostate cancer diagnostics.

    abstract：:Androgen receptors are present in most advanced prostate cancer specimens, having a critical role in development of this type of cancer. For correct prognosis of patient conditions and treatment monitoring, noninvasive imaging techniques have great advantages over surgical procedures. We developed synthetic methodolog...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100289b

    authors： Marom H,Miller K,Bechor-Bar Y,Tsarfaty G,Satchi-Fainaro R,Gozin M

    更新日期：2010-09-09 00:00:00

  • Fluorinated sugar analogues of potential anti-HIV-1 nucleosides.

    abstract：:In order to obtain agents with therapeutic indices superior to those of AZT, FLT, or D4T, several analogues of anti-HIV-1 nucleosides were synthesized. These include 2',3'-dideoxy-2',3' -difluoro-5-methyluridine (13), its arabino analogue 19, arabino-5-methylcytosine analogue 21, 3'-deoxy-2',3'-didehydro-2' -fluorothy...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00109a017

    authors： Huang JT,Chen LC,Wang LB,Kim MH,Warshaw JA,Armstrong D,Zhu QY,Chou TC,Watanabe KA,Matulic-Adamic J

    更新日期：1991-05-01 00:00:00

  • Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6(1a)

    abstract：:The antineoplastic constituents of Combretum caffrum (Eckl. and Zeyh) Kuntze (Combretaceae family), a species indigenous to South Africa, have been investigated. Subsequently we isolated a series of closely related bibenzyls, stilbenes, and phenanthrenes from C. caffrum. Some of the stilbenes proved to be potent antim...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00010a011

    authors： Pettit GR,Singh SB,Boyd MR,Hamel E,Pettit RK,Schmidt JM,Hogan F

    更新日期：1995-05-12 00:00:00

  • Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug Design.

    abstract：:Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00845

    authors： Geist L,Mayer M,Cockcroft XL,Wolkerstorfer B,Kessler D,Engelhardt H,McConnell DB,Konrat R

    更新日期：2017-11-09 00:00:00

  • Structure-activity relationship and molecular mechanisms of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and its analogues.

    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

    pub_type： 杂志文章

    doi：10.1021/jm200764t

    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

  • Design and synthesis of small molecule RhoA inhibitors: a new promising therapy for cardiovascular diseases?

    abstract：:RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200161c

    authors： Deng J,Feng E,Ma S,Zhang Y,Liu X,Li H,Huang H,Zhu J,Zhu W,Shen X,Miao L,Liu H,Jiang H,Li J

    更新日期：2011-07-14 00:00:00

  • Dipeptidyl peptidase IV dependent water-soluble prodrugs of highly lipophilic bicyclic nucleoside analogues.

    abstract：:We present the first report of the application of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to hydroxy-containing drug derivatives. In particular, we applied this strategy to the highly lipophilic antiviral drug family of bicyclic furanopyrimidine nucleoside analogues (BCNA) in order to improve t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm101624e

    authors： Diez-Torrubia A,Balzarini J,Andrei G,Snoeck R,De Meester I,Camarasa MJ,Velázquez S

    更新日期：2011-03-24 00:00:00

  • Synthesis and antineoplastic properties of ether-linked thioglycolipids.

    abstract：:Ether-linked glycero-alpha- and beta-D-glucopyranosides and glycero-1-thio-alpha- and beta-D-glucopyranosides have been synthesized by modifications of the Königs-Knorr procedure, and their antitumor activities have been evaluated. The bioactivities of these compounds have been evaluated in five different cell lines (...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00171a042

    authors： Guivisdalsky PN,Bittman R,Smith Z,Blank ML,Snyder F,Howard S,Salari H

    更新日期：1990-09-01 00:00:00

  • Synthesis of analogues of pepstatin. Effect of structure in subsites P1', P2', and P2 on inhibition of porcine pepsin.

    abstract：:A series of pepstatin analogues having structural variations in the P2', P1', and P2 positions have been synthesized and tested for inhibition of porcine pepsin. The standard peptide for this study was Iva-Sta-Val-Ala-Iaa. Structural variations in the P2' and P1' positions have relatively little effect on Ki; however,...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00360a022

    authors： Rich DH,Salituro FG

    更新日期：1983-06-01 00:00:00

  • Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes.

    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

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00505

    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

  • Bicyclic Helical Peptides as Dual Inhibitors Selective for Bcl2A1 and Mcl-1 Proteins.

    abstract：:A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein-protein interaction was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00010

    authors： D de Araujo A,Lim J,Wu KC,Xiang Y,Good AC,Skerlj R,Fairlie DP

    更新日期：2018-04-12 00:00:00

  • Synthesis and beta-adrenergic blocking activity of new aliphatic oxime ethers.

    abstract：:New beta-adrenergic blocking agents, most of which do not contain an aromatic nucleus, were synthesized. They were derived either from alkylamino-aliphatic oxime ethers or alkylamino-aliphatic ethers. Most active among these are O-[3-(tert-butylamino)-2-hydroxypropyl]acetoxime (8; trachea pA2 = 7.65) and 1-isobutoxy-3...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00180a007

    authors： Leclerc G,Bieth N,Schwartz J

    更新日期：1980-06-01 00:00:00

  • New dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme: rational design, bioavailability, and pharmacological responses in experimental hypertension.

    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

    pub_type： 杂志文章

    doi：10.1021/jm00034a005

    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

  • Discovery of antimycobacterial spiro-piperidin-4-ones: an atom economic, stereoselective synthesis, and biological intervention.

    abstract：:An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is des...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800545k

    authors： Kumar RR,Perumal S,Senthilkumar P,Yogeeswari P,Sriram D

    更新日期：2008-09-25 00:00:00