- Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism
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Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.
- Schramm, Simon,Agnetta, Luca,Bermudez, Marcel,Gerwe, Hubert,Irmen, Matthias,Holze, Janine,Littmann, Timo,Wolber, Gerhard,Tr?nkle, Christian,Decker, Michael
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p. 1349 - 1358
(2019/07/12)
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- 1-(Piperidin-4-yl)-2-benzimidazolone compounds and application thereof
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The invention belongs to the technical field of medicines, and relates to novel 1-(piperidin-4-yl)-2-benzimidazolone compounds, a composition containing the compounds, and a use of the compounds or the composition as human immunodeficiency virus (HIV ) integrase inhibitor. The compounds are used for the antiviral treatment of 2-or-more-years-old HIV-infected persons. The above drugs act on HIV integrase to prevent HIV replication in order to reduce the HIV viral load in blood. The structure of the compounds is represented by general formula (I), and R1 and R2 in the general formula (I) are asdefined in the claims and the description.
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- The preparation method of the deuterium generation of Mauzy is special
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The invention discloses a preparation method of deuterated pimozide. The pimozide-d4 is synthesized from 4-bromopentafluorobenzene-d4 through eight steps. The provided preparation method has the advantages of reasonable technological design, simple operation, easy product separation and purification, easily-available raw materials, high yield, and high purity. The isotope abundance of the obtained target product is high. The prepared stable isotope-labeled pimozide-d4 can be well applied to clinical pharmacokinetics researches, so people can acknowledge the metabolism process and action mechanism of pimozide in human body more precisely and conveniently, and thus the deuterated pimozide has an important application value.
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- Concise and simple synthesis of M1 allosteric agonist TBPB
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A concise and simple synthesis of M1 allosteric agonist 1-(1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d] imidazol-2(3H)-one (TBPB) using economical and commercially available orthophenylenediamine (O-PDA) and Boc piperidone has been described. The disclosed scheme allows synthesizing more analogs that were otherwise difficult to prepare with the original method. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
- Rasheed, Mohammed Abdul,Shaik, Nagul Meera,Nirogi, Ramakrishna
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p. 1796 - 1801
(2013/05/21)
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- Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists
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A novel series of benzimidazolone-containing histamine H 3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki = 0.95 nM and rat AUC = 12.9 μM h.
- Zeng, Qingbei,Rosenblum, Stuart B.,Yang, Zhaoxia,Jiang, Yueheng,McCormick, Kevin D.,Aslanian, Robert G.,Duguma, Luli,Kozlowski, Joseph A.,Shih, Neng-Yang,Hey, John A.,West Jr., Robert E.,Korfmacher, Walter A.,Berlin, Michael,Boyce, Christopher W.
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p. 6001 - 6003
(2013/10/22)
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- Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: Optimization of the 4-substituted piperidine
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In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g., 18 and 29). These studies produced a potent analog (18) which overcomes the instability issues associated with the lead structure 1. A general pharmacophore for the 4-substituted piperidine component of these CGRP receptor antagonists is also presented.
- Burgey, Christopher S.,Stump, Craig A.,Nguyen, Diem N.,Deng, James Z.,Quigley, Amy G.,Norton, Beth R.,Bell, Ian M.,Mosser, Scott D.,Salvatore, Christopher A.,Rutledge, Ruth Z.,Kane, Stefanie A.,Koblan, Kenneth S.,Vacca, Joseph P.,Graham, Samuel L.,Williams, Theresa M.
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p. 5052 - 5056
(2007/10/03)
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- Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors
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A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
- Gustin, Darin J.,Sehon, Clark A.,Wei, Jianmei,Cai, Hui,Meduna, Steven P.,Khatuya, Haripada,Sun, Siquan,Gu, Yin,Jiang, Wen,Thurmond, Robin L.,Karlsson, Lars,Edwards, James P.
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p. 1687 - 1691
(2007/10/03)
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- 2-oxoimidazole derivatives
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The present invention relates to a compound represented by Formula [I] wherein represents an aromatic carbo- or heterocyclic ring which may have a substituent; Cy represents a mono-, bi- or tricyclic aliphatic carbocyclic group having 3 to 20 carbon atoms, which may have a substituent; represents a mono- or bicyclic aliphatic nitrogen-containing heterocyclic group having 3 to 14 carbon atoms, which may have a substituent; R1represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group, a cyclo(lower alkyl) group, an amino group, a lower alkylamino group, a di(lower alkyl)-amino group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di(lower alkyl)carbamoyl group, or a lower alkyl group which may have a substituent; and R2represents a hydrogen atom or a lower alkyl group, a salt or ester thereof, a production process for the same, and an analgesic, a reliever against tolerance to a narcotic analgesic represented by morphine, a reliever against dependence on a narcotic analgesic represented by morphine, an analgesic enhancer, an antiobestic, a drug for ameliorating brain function, a remedy for schizophrenia, a remedy for Parkinsonism, a remedy for chorea, an antidepressant, a remedy for diabetes insipidus, a remedy for polyuria, or a remedy for hypotension, comprising an effective ingredient of the same.
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- Alpha IC adrenergic receptor antagonists
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This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha-1C adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hypertrophy. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha1C receptor subtype without at the same time inducing orthostatic hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.
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- Easy microwave assisted deprotection of N-Boc derivatives
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A simple and efficient method for the cleavage of tert-butoxycarbonyl amides and amines is described, which takes place on silica gel under microwave irradiation.
- Siro, Jorge G.,Martín, Justina,García-Navío, José L.,Remui?an, Modesto J.,Vaquero, Juan J.
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p. 147 - 148
(2007/10/03)
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