- Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
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A series of 1,4-substituted arylalkyl piperazine derivatives were synthesized and studied with the aim to obtain potent P-gp-dependent multidrug-resistant (MDR) reversers. The new compounds were designed on the basis of the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity. All new compounds were active in the pirarubicin uptake assay on the doxorubicin–resistant erythroleukemia K562 cells (K562/DOX). In particular, compounds bearing methoxy aromatic moieties showed fairly high reversal activities. The most potent compounds, 8, 9, 10 and 13, were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) and the inhibition of P-gp-mediated rhodamine-123 (Rhd 123) efflux on the K562/DOX cell line. The results of all pharmacological assays indicated that the combination of a basic piperazine scaffold with arylalkyl residues allowed us to obtain very interesting P-gp modulating compounds. Two long-lasting P-gp pump modulators (9 and 10) were identified; they were able to inhibit remarkably the P-gp substrate rhodamine-123 efflux on the resistant K562/DOX cell line after 60 min. Overall compound 9 appeared the most promising compound being a potent and long-lasting P-gp–dependent MDR modulator.
- Dei, Silvia,Coronnello, Marcella,Bartolucci, Gianluca,Manetti, Dina,Romanelli, Maria Novella,Udomtanakunchai, Chatchanok,Salerno, Milena,Teodori, Elisabetta
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- Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I)
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Kv1.5 potassium channel is an efficacious and safe therapeutic target for the treatment of atrial fibrillation (AF), the most common arrhythmia that threatens human. Herein, by modifying the hit compound 7k from an in-house database, 48 derivatives were synthesized for the assay of their Kv1.5 inhibitory effects by whole cell patch clamp technique. Six compounds which showed better potency than the positive compound dronedarone were selected for the next evaluation of their drug-like properties. Compound 8 exhibited balanced solubility and permeability. It also showed acceptable pharmacodynamics profile with very low acute toxicity. Taking all these data into account, compound 8 can serve as a promising lead for the development of novel therapeutic agent for the treatment of AF.
- Guo, Xiaoke,Ma, Xianglei,Yang, Qian,Xu, Jing,Huang, Lu,Jia, Jianmin,Shan, Jiaojiao,Liu, Li,Chen, Weilin,Chu, Hongxi,Wei, Jinlian,Zhang, Xiaojin,Sun, Haopeng,Tang, Yiqun,You, Qidong
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- 1-Phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl]piperazine derivatives as non-imidazole histamine H3-antagonists
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In this study, a series of 1-phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl] piperazine derivatives has been prepared and in vitro tested as H 3-receptor antagonists (electrically evoked contraction of the guinea pig jejunum). All compounds inve
- Staszewski, Marek,Walczynski, Krzysztof
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p. 1287 - 1304
(2013/04/10)
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- A practical synthesis of sarpogrelate hydrochloride and in vitro platelet aggregation inhibitory activities of its analogues
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A convenient approach for the preparation of sarpogrelate hydrochloride was developed. Two series of sarpogrelate hydrochloride analogues were designed and synthesized in order to improve their platelet aggregation inhibitory activities, biological tests suggested that these compounds have platelet aggregation inhibitory activities to some extent.
- Chen, Guo Hua,Wang, Sheng,Wu, Fei Hua
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scheme or table
p. 287 - 289
(2010/12/20)
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- Synthesis and preliminary pharmacological evaluation of 4′-arylalkyl analogues of clozapine. IV. the effects of aromaticity and isosteric replacement
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We report the synthesis and preliminary pharmacological activity of a new series of tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. These compounds were designed based on a revised structural model, a
- Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Podloucka, Anna,Taylor, David A.
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experimental part
p. 930 - 940
(2009/04/06)
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- Discovery of novel neuronal voltage-dependent calcium channel blockers based on emopamil left hand as a bioactive template
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A series of novel neuronal voltage-dependent calcium channel (VDCC) blockers, with inhibitory activity at low micromolar and moderate solubility in water, was discovered by constructing and screening a focused library based on emopamil (1) left hand (ELH)
- Suzuki, Yuichi,Yamamoto, Noboru,Iimura, Yoichi,Kawano, Koki,Kimura, Teiji,Nagato, Satoshi,Ito, Koichi,Komatsu, Makoto,Norimine, Yoshihiko,Kimura, Manami,Teramoto, Tetsuyuki,Kaneda, Yoshihisa,Hamano, Takeshi,Niidome, Tetsuhiro,Yonaga, Masahiro
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p. 919 - 922
(2007/10/03)
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- N,N-SUBSTITUTED CYCLIC AMINE DERIVATIVES
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N,N-substituted cyclic amine derivatives represented by general formula (VIII) or pharmacologically acceptable salts thereof: wherein A represents aryl, etc.; E represents -CO- or -CHOH-; G represents oxygen, etc.; J represents optionally substituted aryl; R1 represents lower alkyl, etc.; Alk represents linear or branched lower alkylene; n, v, w, x and y independently represent each 0 or 1; and p represents 2 or 3. These compounds or salts thereof are efficacious in treating diseases against which calcium antagonism is efficacious. These diseases include cerebrovascular disorder at the acute stage, cerebral stroke, cerebral infarction, head injury, cerebral nerve cell death, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, brain circulatory disturbance, brain function disturbance, pain, convulsion, schizophrenia, hemicrania, epilepsy, circular psychosis, nerve degeneration diseases, brain ischemia, AIDS, complex dementia, edema, anxiety and diabetic nephropathy.
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- 2-(substituted-1-piperazinyl)[1,2,4]triazolo[1,5-a]pyrimidines
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This disclosure describes novel 2-(4-substituted-1-piperazinyl)[1,2,4]triazolo[1,5-a]pyrimidines useful as hypotensive agents.
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- Pyrazolylpiperazines
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This disclosure describes novel pyrazolylpiperazines useful as hypotensive agents in mammals and as intermediates for the preparation of certain pyrazolo[1,5-a]pryrimidines.
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