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Cambridge MedChem Consulting

Nitro bioisosteres.

At the 17th RSC-SCI Medicinal Chemistry Conference in Cambridge Alexander Pasternak (Merck) gave an excellent talk on their work to identify a potent and selective ROM-K inhibitor as novel diuretics. The ROM-K potassium channel is a member of the inward rectifier family of potassium channels expressed in two regions of the kidney: thick ascending loop of Henle and cortical collecting duct DOI, ROMK participates in potassium recycling across the luminal membrane which is critical for the function of the Na+/K+/2C1" co-transporter, the rate- determining step for salt reuptake in this part of the nephron. At the cortical collecting duct , ROMK provides a pathway for potassium secretion that is tightly coupled to sodium uptake through the amiloride sensitive sodium channel. This makes ROM-K an attractive potassium sparing diuretic target.

To cut a long story short Merck ran a HTS campaign (actually I think they ran two) and the only hit is shown below.


As I am sure all medicinal chemists are aware nitro groups, in particular aromatic nitro groups are well known to be reduced in vivo yielding hydroxylamines and nitrosoamines that are highly reactive species and are known carcinogens. So whilst one nitro in the hit is bad imagine how it feels to have two!

The Merck group however followed this lead up and managed to identify several bioisosteric replacements for the nitro group,


Interestingly there have been two other reported hits for the same target, and these also include nitrobenzenes.


These structures underline the importance of the arylnitro group but also raise a couple of interesting questions, whether nitro compounds should be removed from screening collections? In addition, given the structure of ion channels is often a parallel array of identical proteins forming a pore through the membrane perhaps we should try to populate screening collections with palindromic structures that might bind linking two chains?

I’ll add these to the bioisosteres section at the weekend.