- The Gas-phase Smiles Rearrangement. The Effect of Ring Substitution. An 18O Labelling Study
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The gas-phase Smiles reaction of RC6H4O(CH2)nO(1-) (n = 2 or 3) is an ipso rearrangement which is strongly influenced by the nature of the substituent R.Electron-withdrawing groups enhance the rearrangement.When the substituent R is halogen or Me, and occupies the ortho position, ortho cyclization competes with the Smiles rearrangement.
- Eichinger, Peter C. H.,Bowie, John H.
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- Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor
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Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.
- Fyfe, Tim J.,Kellam, Barrie,Sykes, David A.,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert,Charlton, Steven J.,Mistry, Shailesh N.
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supporting information
p. 9488 - 9520
(2019/11/11)
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- Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer
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Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis of androgens. Recurrence is common and within 2–3?years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies. In order to provide a more effective treatment, we are utilizing an approach that targets a key scaffolding protein, Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane protein that is critical in stabilizing the AR. Herein we report on a new series of Sigma1 compounds for lead optimization derived from a hybrid pharmacophore approach.
- Salvino, Joseph M.,Srikanth, Yellamelli V.V.,Lou, Rongliang,Oyer, Halley M.,Chen, Nan,Kim, Felix J.
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supporting information
p. 2216 - 2220
(2017/04/27)
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- Identification of a new selective dopamine D4 receptor ligand
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The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (K iD4 = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4 = 3.9 nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100 nM (Ki 4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.
- Sampson, Dinithia,Zhu, Xue Y.,Eyunni, Suresh V.K.,Etukala, Jagan R.,Ofori, Edward,Bricker, Barbara,Lamango, Nazarius S.,Setola, Vincent,Roth, Bryan L.,Ablordeppey, Seth Y.
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p. 3105 - 3114
(2014/06/09)
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- Copper(ii)-catalyzed C-O coupling of aryl bromides with aliphatic diols: Synthesis of ethers, phenols, and benzo-fused cyclic ethers
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A highly efficient copper-catalyzed C-O cross-coupling reaction between aryl bromides and aliphatic diols has been developed employing a cheaper, more efficient, and easily removable copper(ii) catalyst. A broad range of aryl bromides were coupled with aliphatic diols of different lengths using 5 mol% CuCl2 and 3 equivalents of K2CO3 in the absence of any other ligands or solvents to afford the corresponding hydroxyalkyl aryl ethers in good to excellent yields. In this newly developed protocol, aliphatic diols have multilateral functions as coupling reactants, ligands, and solvents. The resulting hydroxyalkyl aryl ethers were further readily converted into the corresponding phenols, presenting a valuable alternative way to phenols from aryl bromides. Furthermore, it was demonstrated that they are useful intermediates for more advanced molecules such as benzofurans and benzo-fused cyclic ethers. This journal is
- Liu, Yajun,Park, Se Kyung,Xiao, Yan,Chae, Junghyun
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supporting information
p. 4747 - 4753
(2014/06/24)
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- Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application
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The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R3) at the para-position of the P1′ benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R1) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC50s on wild-type HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS.
- Kesteleyn, Bart,Amssoms, Katie,Schepens, Wim,Hache, Geerwin,Verschueren, Wim,Van De Vreken, Wim,Rombauts, Klara,Meurs, Greet,Sterkens, Patrick,Stoops, Bart,Baert, Lieven,Austin, Nigel,Wegner, J?rg,Masungi, Chantal,Dierynck, Inge,Lundgren, Stina,J?nsson, Daniel,Parkes, Kevin,Kalayanov, Genadiy,Wallberg, Hans,Rosenquist, ?sa,Samuelsson, Bertil,Van Emelen, Kristof,Thuring, Jan Willem
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p. 310 - 317
(2013/02/25)
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- Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents
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Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that haloperidol can serve as a useful lead in the identification and design of new agents that target multiple receptors associated with antipsychotic pharmacology.
- Peprah, Kwakye,Zhu, Xue Y.,Eyunni, Suresh V.K.,Setola, Vincent,Roth, Bryan L.,Ablordeppey, Seth Y.
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experimental part
p. 1291 - 1297
(2012/04/11)
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- Structure-activity relationship studies of SYA 013, a homopiperazine analog of haloperidol
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Structure-activity relationship studies on 4-(4-(4-chlorophenyl)-1,4- diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one (SYA 013), a homopiperazine analog of haloperidol has resulted in an understanding of the effect of structural modifications on binding affinity at dopamine and serotonin receptor subtypes. Further exploration, using bioisosteric replacement strategies has led to the identification of several new agents including compounds 7, 8, 11 and 12 which satisfy the initial criteria for further exploration as new antipsychotic agents. In addition, compound 18, a D3 selective tropanol, has been identified as having the potential for further optimization into a useful drug which may combat neuropsychiatric diseases.
- Peprah, Kwakye,Zhu, Xue Y.,Eyunni, Suresh V.K.,Etukala, Jagan R.,Setola, Vincent,Roth, Bryan L.,Ablordeppey, Seth Y.
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experimental part
p. 1671 - 1678
(2012/04/10)
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- Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: Optimization of in vitro activity
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Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.
- Peters, Jens-Uwe,Kühne, Holger,Dehmlow, Henrietta,Grether, Uwe,Conte, Aurelia,Hainzl, Dominik,Hertel, Cornelia,Kratochwil, Nicole A.,Otteneder, Michael,Narquizian, Robert,Panousis, Constantinos G.,Ricklin, Fabienne,R?ver, Stephan
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scheme or table
p. 5426 - 5430
(2010/12/25)
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- 5-HT4 agonists and antagonists
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Compounds of formula I: are used as antagonists and partial agonists for the serotonin receptor 5-HT4 and provide therapeutic methods for treatment of disorders caused by or affected by dysfunction of the 5-HT4 receptor.
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