- Synthesis, Structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds
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We have previously shown that a "reversed chloroquine (RCQ)" molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in P. falciparum (Burgess, S. J.; Selzer, A.; Kelly, J. X.; Smilkstein, M. J.; Riscoe, M. K.; Peyton, D. H. J. Med. Chem. 2006, 49, 5623. Andrews, S.; Burgess, S. J.; Skaalrud, D.; Kelly, J. X.; Peyton, D. H. J. Med. Chem. 2010, 53, 916). Here, we present an investigation into the Structure-activity relationship of the RCQ structures, resulting in an orally active molecule with good in vitro and in vivo antimalarial activity. We also present evidence of the mode of action, indicating that the RCQ molecules inhibit hemozoin formation in the parasite's digestive vacuole in a manner similar to that of chloroquine.
- Burgess, Steven J.,Kelly, Jane X.,Shomloo, Shawheen,Wittlin, Sergio,Brun, Reto,Liebmann, Katherine,Peyton, David H.
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experimental part
p. 6477 - 6489
(2010/11/05)
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- Discovery of benzhydrylpiperazine derivatives as CB1 receptor inverse agonists via privileged structure-based approach
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The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB1 receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB1 receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague-Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure-activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed.
- Meng, Tao,Wang, Jue,Peng, Hongli,Fang, Guanghua,Li, Min,Xiong, Bing,Xie, Xin,Zhang, Yongliang,Wang, Xin,Shen, Jingkang
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scheme or table
p. 1133 - 1139
(2010/05/02)
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- Hybrid approach for the design of highly affine and selective dopamine D3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands
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A series of compounds containing privileged scaffolds of the known histamine H1 receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D3 receptor. A pharmacological screening was carried out at dopamine D2 and D3 receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D3receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD3 Ki = 0.3 nM; hD2 Ki = 703 nM), leading to a selectivity ratio of 2343.
- Sasse, Britta C.,Mach, Ulrich R.,Leppaenen, Jukka,Calmels, Thierry,Stark, Holger
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p. 7258 - 7273
(2008/03/27)
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- 2-ureido-benzamide derivatives
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This invention is concerned with 2-ureido-benzamide compounds of the formula (1) STR1 in which R1 is H, halogen atom, (C1 -C4)alkyl, (C1 -C4)alkoxy or (C1 -C4)dialkylamino and R2 is H, halogen atom, hydroxy, nitro, (C1 -C4)alkyl, (C1 -C4)alkoxy, (C3 -C6) cycloalkylmethoxy, (C1 -C4) alkylthio, (C1 -C4) alkylsulfinyl, (C1 -C4)alkylsulfonyl or STR2 wherein j is an integer of from 0 to 2 and R3 and R4 are each independently H, (C1 -C4)alkyl, (C1 -C4)alkanoyl, (C1 -C4)alkylsulfonyl or (C1 -C4)alkylcarbamoyl, NR3 R4 can to form a pyrrolidine, piperidine, morpholine, imidazole or pyrazole ring; X is a (C3 -C15)alkyl, (C3 -C6) cycloalkyl, (C3 -C6) cycloalkylmethyl, ω-(C1 -C4) alkoxy-(C1 -C4) alkyl group or STR3 wherein k is an integer of from 1 to 4 and R5 and R6 are each independently H, Y is H or (C1 -C4)alkyl and Z is STR4 wherein m is an integer of from 0 to 4.
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