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Tuesday 17 May 2016

MK-7145

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2D chemical structure of 1255204-84-2

MK-7145,

cas: 1255204-84-2

1(3H)-Isobenzofuranone, 5,5'-(1,4-piperazinediylbis((1R)-1-hydroxy-2,1-ethanediyl))bis(4-methyl-

Abstract Image
ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure

Departments of Discovery Chemistry, Ion Channels, §In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, New Jersey 07033, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00122
Publication Date (Web): May 12, 2016
Copyright © 2016 American Chemical Society
*Tel: 908-740 4932. E-mail: haifeng_tang@merck.com.
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 Stiniva, Croatia,  island


 Map of Stiniva, Croatia,  island

Welcome to paradise: Croatian island is voted best beach in Europe (no prizes for guessing why) 

  • Stiniva has been named the top sandy offering in Europe by tourism organisation European Best Destinations
  • It is only accessible by hiking on a steep and narrow path, or by taking a taxi boat from the nearby Rukavac cove
  • Those keen for a visit have to head to Vis, where the sandy retreat is situated on the southern part of the island 
  • It is breathtakingly secluded with a sea entrance that's just 16 feet wide - and the waters there are crystal clear 





If you are still deciding where to jet off to this summer, you could do a lot worse than Stiniva in Croatia, because it has been voted the best beach in Europe.
And with its crystal clear waters, white sands and a stunning clifftop backdrop it is clear to see why the seaside paradise topped the chart.
Much of its charm stems from just how secluded and peaceful it is. It's accessible only by hiking along a steep and narrow path, or by taking a taxi boat from the nearby Rukavac cove. Those who make the effort will be rewarded with an exquisite patch of coastline with a sea entrance of less than 16 feet. 
If you are still deciding where to jet off to this summer, why not aim for Stiniva in Croatia, which has been voted the best beach in Europe
With its crystal clear waters, white sands and a stunning clifftop backdrop, it is clear to see why the seaside paradise topped the chart
With its crystal clear waters, white sands and a stunning clifftop backdrop, it is clear to see why the seaside paradise topped the chart
To access Vis, and the spectacular Stiniva, visitors can take a two-hour ferry from the harbour in Split
To access Vis, and the spectacular Stiniva, visitors can take a two-hour ferry from the harbour in Split
As far as tourism organisation European Best Destinations is concerned, it's fully deserving of its 2016 Best Beach in Europe gong.
Those keen for a visit have to head to Vis, where the sandy retreat is situated on the southern part of the island, close to the village of Žužec.
A visit to this award-winning beach would not be complete without exploring the island – perhaps hire a scooter and take in the towns of Vis and Komiza, before heading north to the vineyard-strewn country of Plisko Polje. 
To access Vis, and the spectacular Stiniva, visitors can take a two-hour ferry from the harbour in Split. 
Accessible only by hiking on a steep and narrow path, or by taking a taxi boat from the nearby Rukavac cove, this exquisite patch of coastline is definitely worth the effort it takes to reach it
Accessible only by hiking on a steep and narrow path, or by taking a taxi boat from the nearby Rukavac cove, this exquisite patch of coastline is definitely worth the effort it takes to reach it
Located away from the busier beaches, Stiniva's peaceful surroundings saw it gain the accolade of 2016 Best Beach in Europe by tourism organisation European Best Destinations
Located away from the busier beaches, Stiniva's peaceful surroundings saw it gain the accolade of 2016 Best Beach in Europe by tourism organisation European Best Destinations
Those keen for a visit have to head for the island of Vis, where the sandy retreat is situated on the southern part of the island, close to the village of ¿u¿ec
Those keen for a visit have to head for the island of Vis, where the sandy retreat is situated on the southern part of the island, close to the village of Žužec
 

 
 

 

 
 



 



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