;
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Cc1c(ccc2c1COC2=O) [C@H](CN3CCN(CC3) C[C@@H](c4ccc5c(c4C) COC5=O) O) O
Stiniva, Croatia, island
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MK-7145,
cas: 1255204-84-2
1(3H)-Isobenzofuranone, 5,5'-(1,4-piperazinediylbis((1R)-1-hydroxy-2,1-ethanediyl))bis(4-methyl-
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.
Cc1c(ccc2c1COC2=O)
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
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
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 Žužec
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