183500-37-0Relevant articles and documents
Highly improved antiparasitic activity after introduction of an N -benzylimidazole moiety on protein farnesyltransferase inhibitors
Bosc, Damien,Mouray, Elisabeth,Cojean, Sandrine,Franco, Caio Haddad,Loiseau, Philippe M.,Freitas-Junior, Lucio H.,Moraes, Carolina Borsoi,Grellier, Philippe,Dubois, Jo?lle
supporting information, p. 173 - 186 (2016/01/25)
In our search for new protein farnesyltransferase inhibitors with improved antiparasitic activities, we modified our previously developed 3-arylthiophene series of inhibitors by replacing the thioisopropyl group by different substituted imidazolylmethanamino moieties. Twenty four new derivatives were synthesized and evaluated against human and parasite farnesyltransferases, and their anti-parasitic activity was determined against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani. Introduction of a N-p-substituted-benzylimidazole led to significantly increase the inhibition of parasite proliferation in the submicromolar range. The structure of the best inhibitors was parasite dependent. Three compounds possess IC50 values at the same range as the reference miltefosine against L. donovani proliferation and other new derivatives display high level of anti-trypanosomal activity against T. cruzi, higher or in the same order of magnitude as the reference compounds benznidazole and nifurtimox.
Synthesis, Biological Evaluation, and Molecular Modeling of 1 -Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)
Roumen, Luc,Peeters, Joris W.,Emmen, Judith M. A.,Beugels, Ilona P. E.,Custers, Erica M. G.,De Gooyer, Marcel,Plate, Ralf,Pieterse, Koen,Hilbers, Peter A. J.,Smits, Jos F. M.,Vekemans, Jef A. J.,Leysen, Dirk,Ottenheijm, Harry C. J.,Janssen, Henk M.,Rob Hermans
experimental part, p. 1712 - 1725 (2010/07/17)
Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved, with mineralocorticoid, receptor antagonists, however, aldosterone synthase (CYP 11B2) inhibitors may offer a promising alternative. In this study, we used three-dimensional modeling of CYP11B2 to model, the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles. Their syntheses, in vitro inhibitor potencies, and in silico docking are described. Some promising CYP11B2 inhibitors were identified, with our novel lead, MOERAS 115 (4-((5-phenyl-1H-imidazol-1-yl)methyl) benzonitrile) displaying an IC50 for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC 50 for CYP11B26.0 nM, selectivity 19.8). Molecular docking of the inhibitors in the models enabled us to generate posthoc hypotheses on their binding modes, providing a valuable basis for future studies and further design of CYP11B2 inhibitors.
N-benzyl imidazole derivatives and their use as aldosterone synthase inhibitors
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Page/Page column 13, (2009/09/26)
The invention relates to the use of a N-benzyl 5-substituted imidazole derivative having the general formula I wherein R is (C1-3)alkyl, (C1-3)alkyloxy, halogen, nitro or cyano; R1 is (C1-6)alkyl, optionally substituted with OH, (C1-3)alkyloxy, (C1-3)alkylcarbonyloxy, (C1-3)alkyloxycarbonyl or halogen, or (C1-3)alkyloxycarbonyl; or R1 is phenyl, optionally substituted with 1-3 substituents independently selected from (C1-3)alkyl, (C1-3)alkyloxy, hydroxylmethyl and halogen; or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder or disease in a subject mediated by aldosterone synthase or responsive to inhibition of aldosterone synthase.
Structurally simple inhibitors of lanosterol 14α-demethylase are efficacious in a rodent model of acute Chagas disease
Suryadevara, Praveen Kumar,Olepu, Srinivas,Lockman, Jeffrey W.,Ohkanda, Junko,Karimi, Mandana,Verlinde, Christophe L. M. J.,Kraus, James M.,Schoepe, Jan,Van Voorhis, Wesley C.,Hamilton, Andrew D.,Buckner, Frederick S.,Gelb, Michael H.
experimental part, p. 3703 - 3715 (2010/04/24)
We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14α-demethylase (L14DM). The compounds have a simple structure compared to posaconazole, another L14DM inhibitor that is an anti-Chagas drug candidate. Several compounds display potency for killing T. cruzi amastigotes in vitro with values of EC 50 in the 0.4-10 nM range. Two compounds were selected for efficacy studies in a mouse model of acute Chagas disease. At oral doses of 20-50 mg/kg given after establishment of parasite infection, the compounds reduced parasitemia in the blood to undetectable levels, and analysis of remaining parasites by PCR revealed a lack of parasites in the majority of animals. These dialkyl imidazoles are substantially less expensive to produce than posaconazole and are appropriate for further development toward an anti-Chagas disease clinical candidate.
Novel N-(4-piperidinyl)benzamide antimalarials with mammalian protein farnesyltransferase inhibitory activity
Ryckebusch, Adina,Gilleron, Pauline,Millet, Regis,Houssin, Raymond,Lemoine, Amelie,Pommery, Nicole,Grellier, Philippe,Sergheraert, Christian,Henichart, Jean-Pierre
, p. 1324 - 1326 (2007/10/03)
Protein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations.
Method of treating cancer
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Page/Page column 93, (2010/02/12)
The present invention relates to methods of treating cancer using a combination of a compound which is an antineoplastic agent and a compound which is a inhibitor of prenyl-protein transferase, which methods comprise administering to said mammal, either s
Potent and selective farnesyl transferase inhibitors
Millet, Régis,Domarkas, Juozas,Houssin, Raymond,Gilleron, Pauline,Goossens, Jean-Fran?ois,Chavatte, Philippe,Logé, Cédric,Pommery, Nicole,Pommery, Jean,Hénichart, Jean-Pierre
, p. 6812 - 6820 (2007/10/03)
We recently described a novel series of CA1A2X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A1A 2 residue. Extensive exploration of structure-activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC50 = 4.60 nM on isolated enzyme, EC50 = 20.0 nM for growth inhibition on a tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.
Novel aminophenyl piperazine or aminophenyl piperidine derivatives inhibiting prenyl transferase proteins and method for preparing same
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Page/Page column 29, (2008/06/13)
The invention concerns compounds corresponding to general formula (I), wherein, in particular: W represents hydrogen, COR6, CSR6, SO2R6, CO(CH2)nR6, (CH2)nR7; X represents CH or N; Y represents (CH2)n, CO, CH2CO, CH═CHCO, CH2CH2CO; Z represents a heterocycle. When Z=pyridine, then Y is other than CO. R1 represents hydrogen, C1-C6 alkyl, halogen OCH3, CF3; R2 and R3, identical or different, represent hydrogen, C1-C6 alkyl; R4 represents a) hydrogen, b) C1-C6 alkyl, c) an aryl, d) a heterocycle; R5 represents hydrogen, COR7R8, SO2R7, CO(CH2)nSR7, CO(CH2)nOR7, CONR7R8, CO(CH2)mCOR7; R6 represents a) a phenyl or a naphthyl, b) a C1-C6 alkyl, a cycloalkyl, c) a heterocycle, d) NR7R8; R7 and R8, identical or different, represent a) hydrogen, C1-C15 alkyl, b) a heterocycle, c) an aryl; n represents 0 to 10; m represents 2 to 10; provided that when Z represents a quinozaline or benzimidazole group, then R5 is other than CH2Ph or methyl and n is other than zero.
Novel benzothienyl or indole derivatives, preparation and use thereof as inhibitors of prenyl transferase proteins
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Page 15, (2010/02/08)
The invention concerns compounds of general formula (1), wherein, in particular; W represents H, SO2R5. CO(CH2)nR5, (CH2)nR6, CS(CH2)nR5; X represents S or NH; Y represents (CH2)p, CO, (CH2)pCO, CH═CH—CO; Z represents a hetcrocycle, imidazole, benzimidazole, isoxazole, tetrazole, oxadiazole, thiadazole, pyridine, quinazoline, quinoxaline, quinoline, thiophene; R1 represents COOR6, CONR6R7, CO—NH—CH(R6)—COOR7, CH2NR6R7, CH2OR6, (CH2)pR6, CH═CHR6; R2 represents in particular hydrogen, C1-C10 alkyl, a substituted or unsubstituted phenyl; R5 and R6 represents hydrogen, C1—C6 alkyl; R5 represents a substituted or unsubstituted phenyl or naphthyl; R6 and R7, identical or different, represent hydrogen, C1—C15 alkyl, a hetcrocycle. an aryl; n represents 0 to 10; p represents 1 to 6.
Design, synthesis, and activity of 4-quinolone and pyridone compounds as nonthiol-containing farnesyltransferase inhibitors
Li, Qun,Claiborne, Akiyo,Li, Tongmei,Hasvold, Lisa,Stoll, Vincent S.,Muchmore, Steven,Jakob, Clarissa G.,Gu, Wendy,Cohen, Jerry,Hutchins, Charles,Frost, David,Rosenberg, Saul H.,Sham, Hing L.
, p. 5367 - 5370 (2007/10/03)
As a part of our efforts to identify potent inhibitors of farnesyltransferase (FTase), modification of the structure of tipifarnib through structure-based design was undertaken by replacing the 2-quinolones with 4-quinolones and pyridones, and subsequent
