Utilization of Halogen Bond in Lead Optimization: A Case Study of Rational Design of Potent Phosphodiesterase Type 5 (PDE5) Inhibitors

2011 ◽  
Vol 54 (15) ◽  
pp. 5607-5611 ◽  
Author(s):  
Zhijian Xu ◽  
Zheng Liu ◽  
Tong Chen ◽  
TianTian Chen ◽  
Zhen Wang ◽  
...  
Keyword(s):  
Rational Design ◽  
Halogen Bond ◽  
Lead Optimization ◽  
Pde5 Inhibitors ◽  
Phosphodiesterase Type

Legalization in context: The design of the WTO’s dispute settlement system

2017 ◽  
Vol 19 (2) ◽  
pp. 304-319 ◽  
Author(s):  
Manfred Elsig
Keyword(s):  
Rational Design ◽  
Dispute Settlement ◽  
The United States ◽  
Settlement System ◽  
Trading System ◽  
Wto Dispute Settlement ◽  
Multilateral Trading System ◽  
The Creation ◽  
Dispute Settlement System

This article asks why the dispute settlement provisions of the multilateral trading system underwent significant reforms during the negotiations that led to the creation of the World Trade Organization (WTO) in 1995. Why did the leading trading powers accept a highly legalized system that departed from established political–diplomatic forms of settling disputes? The contribution of this article is threefold. First, it complements existing accounts that exclusively focus on the United States with a novel explanation that takes account of contextual factors. Second, it offers an in-depth empirical case study based on interviews with negotiators who were involved and novel archival evidence on the creation of the new WTO dispute settlement system. Third, by unpacking the long-standing puzzle of why states designed a highly legalized system, it addresses selected blind spots of the legalization and the rational design literatures with the aim of providing a better understanding about potential paths leading toward significant changes in legalization.

Selectivity of sildenafil and other phosphodiesterase type 5 (PDE5) inhibitors against all human phosphodiesterase families

2002 ◽  
Vol 1 (1) ◽  
pp. 63 ◽  
Author(s):  
Eugene Gbekor ◽  
Sue Betheil ◽  
Lindsay Fawcett ◽  
Natalie Mount ◽  
Stephen Phillips
Keyword(s):  
Pde5 Inhibitors ◽  
Phosphodiesterase Type

Addressing Genotoxicity Risk in Lead Optimization: A PDE10A Inhibitor Case Study

2018 ◽  
pp. 581-602
Author(s):  
Bie M. P. Verbist ◽  
Marjolein Crabbe ◽  
Freddy Van Goethem ◽  
Hinrich W. H. Göhlmann
Keyword(s):  
Lead Optimization

scholarly journals Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2213 ◽  
Author(s):  
Alessandro Dessì ◽  
Paola Peluso ◽  
Roberto Dallocchio ◽  
Robin Weiss ◽  
Giuseppina Andreotti ◽  
...  
Keyword(s):  
High Performance ◽  
Rational Design ◽  
Halogen Bond ◽  
Coupling Reaction ◽  
Docking Studies ◽  
Binding Modes ◽  
Design Synthesis ◽  
In Silico Docking ◽  
Amyloid Fibril Formation ◽  
The Right

The 3,3′,5,5′-tetrachloro-2-iodo-4,4′-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3′,5,5′-tetrachloro-2-iodo-2′-substituted-4,4′- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2′-substituent. The corresponding racemates, along with other five chiral 4,4′-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4′-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3′,5,5′-tetrachloro-2′-(4-hydroxyphenyl)-2-iodo-4,4′-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4′-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4′-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

scholarly journals Audiometry Results and TEOAE and DPOAE Amplitudes in Men Taking a Phosphodiesterase Type 5 Inhibitor for Erectile Dysfunction

2017 ◽  
Vol 96 (7) ◽  
pp. E34-E39 ◽  
Author(s):  
Sertan Öntepeli ◽  
Nuray Bayar Muluk ◽  
Devrim Tuğlu ◽  
Timuçin Şipal
Keyword(s):  
Erectile Dysfunction ◽  
Otoacoustic Emissions ◽  
Pde5 Inhibitor ◽  
Post Treatment ◽  
Guanosine Monophosphate ◽  
Pde5 Inhibitors ◽  
Cochlear Blood Flow ◽  
Distortion Product ◽  
Phosphodiesterase Type 5 Inhibitor ◽  
Phosphodiesterase Type

We conducted a prospective study of transient evoked otoacoustic emissions (TEOAEs) and distortion-product otoacoustic emissions (DPOAEs) in men who were taking an oral phosphodiesterase type 5 (PDE5) inhibitor for erectile dysfunction. Our study group was made up of 30 men (60 ears), aged 34 to 60 years (mean: 50.9). They were randomly divided into three groups; 10 men were given sildenafil (Viagra) at 50 mg twice a week, 10 were given tadalafil (Cialis) at 20 mg twice a week, and 10 were given vardenafil (Levitra) at 20 mg twice a week. All patients took their drug for 3 weeks, for a total of 6 tablets for each patient. Audiometric tests and TEOAE and DPOAE measurements were performed before and after treatment. Post-treatment audiometry demonstrated improvement in hearing in all three groups. However, post-treatment TEOAE amplitudes and DPOAE amplitudes differed among the three groups; they were significantly higher in the sildenafil group at 1.0 kHz and the same in the tadalafil group; in the vardenafil group, the DPOAE amplitude was significantly lower at 3.0 kHz while there was no change in the TEOAE amplitude. We speculate that the possible mechanism for these findings is that PDE5 inhibitors block degradation of cyclic guanosine monophosphate (cGMP) and induce dilation of the cochlear microcirculation, resulting in an increase in cochlear blood flow. We also believe that the decrease in DPOAE amplitudes at 3.0 kHz seen in the vardenafil group may be related to an accumulation of nitric oxide/cGMP complex, which is toxic to the cochlea; however, since there was no change in TEOAE amplitude in the vardenafil group, this influence may be minimal. Further studies are needed to obtain a more comprehensive assessment of the effects of PDE5 inhibitors on hearing with the use of higher doses and longer durations of therapy.

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