- Synthesis and structure-activity relationships of new 2-phenoxybenzamides with antiplasmodial activity
-
The 2-phenoxybenzamide 1 from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tert-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 μM) and very low cytotoxicity (L-6 cells IC50 = 124.0 μM) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.
- Dolensky, Johanna,Hermann, Theresa,Hochegger, Patrick,Kaiser, Marcel,M?ser, Pascal,Pferschy-Wenzig, Eva-Maria,Saf, Robert,Seebacher, Werner,Weis, Robert
-
-
- MONOACYLGLYCEROL LIPASE INHIBITORS
-
Provided are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof: Also provided are compositions comprising compounds of formula (I). The compounds and compositions are also provided for use as medicaments, for example as medicaments useful in the treatment of a condition modulated by monoacylglycerol lipase (MAGL). Also provided are the use of compounds and compositions for the inhibition of monoacylglycerol lipase (MAGL).
- -
-
Paragraph 0111-0112; 0141; 0153-0154; 0200-0201
(2021/09/09)
-
- Covalent inhibition of the histamine H3 receptor
-
Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H3R was validated with washout experiments and leads to inverse agonism on H3R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H3R conformation and to study the consequences of prolonged inhibition of the H3R.
- Wágner, Gábor,Mocking, Tamara A.M.,Kooistra, Albert J.,Slynko, Inna,ábrányi-Balogh, Péter,Keser u, Gy?rgy M.,Wijtmans, Maikel,Vischer, Henry F.,de Esch, Iwan J.P.,Leurs, Rob
-
-
- 4-Substituted-2-phenylquinazolines as inhibitors of BCRP
-
We investigated several 2-phenylquinazolines with different substitutions at position 4 for their BCRP inhibition. Compounds with phenyl ring attached via an amine-containing linker at position 4 were found to be potent inhibitors of BCRP. In general compounds with meta substitution of phenyl ring at position 4 were found to have higher inhibitory effect, compound 12 being the most potent and selective towards BCRP.
- Juvale, Kapil,Wiese, Michael
-
p. 6766 - 6769,4
(2012/12/12)
-
- Discovering Small-Molecule Estrogen Receptor α/Coactivator Binding Inhibitors: High-Throughput Screening, Ligand Development, and Models for Enhanced Potency
-
Small molecules, namely coactivator binding inhibitors (CBIs), that block estrogen signaling by directly inhibiting the interaction of the estrogen receptor (ER) with coactivator proteins act in a fundamentally different way to traditional antagonists, which displace the endogenous ligand estradiol. To complement our prior efforts at CBI discovery by denovo design, we used high-throughput screening (HTS) to identify CBIs of novel structure and subsequently investigated two HTS hits by analogue synthesis, finding many compounds with low micromolar potencies in cell-based reporter gene assays. We examined structure-activity trends in both series, using induced-fit computational docking to propose binding poses for these molecules in the coactivator binding groove. Analysis of the structure of the ER-steroid receptor coactivator (SRC) complex suggests that all four hydrophobic residues within the SRC nuclear receptor box sequence are important binding elements. Thus, insufficient water displacement upon binding of the smaller CBIs in the expansive complexation site may be limiting the potency of the compounds in these series, which suggests that higher potency CBIs might be found by screening compound libraries enriched with larger molecules.
- Sun, Aiming,Moore, Terry W.,Gunther, Jillian R.,Kim, Mi-Sun,Rhoden, Eric,Du, Yuhong,Fu, Haian,Snyder, James P.,Katzenellenbogen, John A.
-
scheme or table
p. 654 - 666
(2012/01/05)
-
- Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists
-
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.
- Sasmal, Pradip K.,Sasmal, Sanjita,Rao, P. Tirumala,Venkatesham,Roshaiah,Abbineni, Chandrasekhar,Khanna, Ish,Jadhav, Vikram P.,Suresh,Talwar, Rashmi,Muzeeb, Syed,Receveur, Jean-Marie,Frimurer, Thomas M.,Rist, ?ystein,Elster, Lisbeth,H?gberg, Thomas
-
scheme or table
p. 5443 - 5448
(2011/01/03)
-
- Unique spirocyclopiperazinium salt III: Further investigation of monospirocyclopiperazinium (MSPZ) salts as potential analgesics
-
Two novel classes of monospirocyclopiperazinium salts were designed, synthesized, and evaluated for their in vivo analgesic activities. Some interesting structure-activity relationships are revealed: (1) Spirocyclopiperazinium moiety is favorable to improve the analgesic activity; (2) The size and conformation of spirocyclopiperazinium moiety significantly affects the analgesic activity; (3) Phenylethyl group of 3d is a crucial pharmacophore. Among the compounds synthesized, 3d exhibited the most potent activity with low toxicity. Further antinociceptive mechanism studies of 3d showed that these compounds will be a new kind of analgesics.
- Sun, Qi,Yue, Cai-Qin,Ye, Jia,Li, Chang-Ling,Cheng, Tie-Ming,Li, Run-Tao
-
p. 6245 - 6249
(2008/04/07)
-
- An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression
-
We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4- cyclohexylmethanesulfonylaminobutyl)-piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs α1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.
- Becker, Oren M.,Dhanoa, Dale S.,Marantz, Yael,Chen, Dongli,Shacham, Sharon,Cheruku, Srinivasa,Heifetz, Alexander,Mohanty, Pradyumna,Fichman, Merav,Sharadendu, Anurag,Nudelman, Raphael,Kauffman, Michael,Noiman, Silvia
-
p. 3116 - 3135
(2007/10/03)
-
- 3,4-dihydro-2-naphthamide derivatives as selective dopamine D3 ligands
-
The invention relates to 3,4-dihydro-2-naphthamide derivatives of formula (I), pharmaceutical compositions containing them and their therapeutic applications as partial agonists or antagonists of the dopamine D3 receptor for the treatment of neuropsychological disorders.
- -
-
Page/Page column 7; 12
(2008/06/13)
-
- BENZIMIDAZOLE DERIVATIVES AND THEIR USE FOR MODULATING THE GABAA RECEPTOR COMPLEX
-
This invention relates to novel benzimidazole derivatives, pharmaceutical compositions containing these compounds, and methods of treatment therewith. The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, and in particular for combating anxiety and related diseases.
- -
-
Page/Page column 15
(2010/11/24)
-
- Compounds derived from aryl carbamates, preparation thereof and uses of same
-
The invention concerns novel compounds, preparation and uses of same, particularly therapeutic. More particularly, the invention concerns compounds derived from arylcarbamates, preparation and uses of same, particularly in the field of human or animal health. The inventive compounds are preferably ligands of serotoninergic 5-HT4 receptors, and can therefore be used in the therapeutic or prophylactic treatment of any disorder involving a 5-HT4 receptor. The invention also relates to pharmaceutical compositions comprising such compounds, preparation and uses thereof, and treatment methods using said compounds.
- -
-
Page/Page column 9
(2010/02/14)
-
- NOVEL BENZIMIDAZOLE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS COMPRISING THESE COMPOUNDS
-
The present invention relates to novel benzimidazole derivatives of the formula (I) as defined in the description and in the claims, pharmaceutical compositions containing these compounds, and methods of treatment therewith. The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, and in particular for inducing and maintaining anaesthesia, sedation and muscle relaxation, as well as for combating febrile convulsions in children. The compounds of the invention may also be used by veterinarians.
- -
-
-
- Aryl carbamate derivatives, preperation and use thereof
-
The present invention relates to novel compounds, the preparation and use, particularly therapeutic, thereof. More specifically, it relates to compounds derived from aryl carbamates, the preparation and use thereof, particularly in the field of human and animal health. The compounds according to the invention are preferably 5-HT4 serotoninergic receptor ligands and can therefore be used in the therapeutic or prophylactic treatment of any disorder involving a 5-HT4 receptor. The invention also relates to pharmaceutical compositions comprising such compounds, the preparation and use thereof and treatment methods using said compounds.
- -
-
Page/Page column 37
(2010/02/06)
-
- Discovery of a potent and selective αvβ3 integrin antagonist with strong inhibitory activity against neointima formation in rat balloon injury model
-
A new series of phenylpiperazine-based derivatives with strong antagonistic activity for αvβ3 integrin were synthesized. Of these derivatives, the fluorine-substituted compound 8 showed strong inhibitory activity and high selectivity for αvβ 3 integrin receptor (IC50=0.055nM). In vivo evaluation of the antistenotic effects of 8 indicated that this compound significantly inhibits neointima formation in rat balloon injury model.
- Iwama, Seiji,Kitano, Tomoko,Fukuya, Fumiyo,Honda, Yayoi,Sato, Yuji,Notake, Mitsue,Morie, Toshiya
-
p. 2567 - 2570
(2007/10/03)
-
- Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
-
The present invention relates to novel benzimidazole derivatives, pharmaceutical composition containing these compounds, and methods of treatment therewith. The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABA receptor complex, and in particular for inducing and maintaining anesthesia, sedation and muscle relaxation, as well as for combating febrile convulsions in children. The compounds of the invention may also be used by veterinarians.
- -
-
-
- Pyrimidinylpyrazole derivatives
-
The present invention provides a novel compound which is represented by formula (I): STR1 wherein preferable examples of R1 to R6 are as follows; R1 and R2 are each an alkyl group optionally substituted by a halogen atom, an amino group, a hydroxyl group, an alkoxyl group or a thiol group, a hydrogen atom, a halogen atom or an alkoxyl group; R3 is a hydrogen atom; R4 is a methyl group; R5 is a hydrogen atom or an alkyl group; and R6 is a group of the formula: STR2 wherein Z is a phenyl group; and has an antitumor effect.
- -
-
-
- Use of 2-Oxazolidinones As Latent Aziridine Equivalents. III. Preparation of N-Substituted Piperazines.
-
A number of N-aryl and N-alkyl substituted piperazines 1 were prepared from variously substituted 2-oxazolidinone derivatives 3.The method involved treatment of 3 with HBr in glacial acetic acid followed by heating the resulting ring-opened salts 5 in alcoholic solvent.The piperazines 1a-1q were isolated by crystallization in yields ranging from 23-91percent.
- Poindexter, Graham S.,Bruce, Marc A.,LeBoulluec, Karen L.,Monkovic, Ivo
-
p. 7331 - 7334
(2007/10/02)
-
- Antiviral agents
-
Antiviral compounds (I): the symbols being as defined in the specification, are efficacious against infections caused by a variety of DNA viruses, RNA viruses and retroviruses. Other specified compounds also exhibit activity. The compounds have a wider spectrum of activity than known antiviral substances.
- -
-
-
- Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy
-
Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (o-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.
- Martin,Elgin Jr.,Mathiasen,Davis,Kesslick,Baldy,Shank,DiStefano,Fedde,Scott
-
p. 1052 - 1056
(2007/10/02)
-