Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores

Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic

“…Through extensive structure−activity relationship (SAR) studies of head groups by parallel synthesis, we found that, in general, the most-potent pharmacophores contained heterocycles with or without attached heteroatoms or nitrile groups. 9,10 Unfortunately, compounds with these head groups usually displayed poor-to-moderate hERG selectivity.…”

“…Thiazide diuretics such as hydrochlorothiazide (HCTZ) and loop diuretics such as furosemide are important classes of therapeutics for human diseases such as chronic heart failure and hypertension. , A liability of thiazide and loop diuretics is that while eliciting natriuretic effects, they also increase urinary potassium loss (kaliuresis), leading to the risk of potentially life-threatening hypokalemia . Our laboratory has recently focused on the development of a selective renal outer medullary potassium channel (ROMK, Kir1.1) inhibitors which act as new mechanism diuretics by inhibiting Na reabsorption while minimizing kaliuresis. − Thus, ROMK inhibitors as new diuretics could potentially avoid the risk of hypokalemia and provide an opportunity for improved safety over currently available diuretics in the treatment of hypertension and congestive heart failure …”

“…However, its reduced ROMK inhibitory potency led to an unacceptably higher projected human dose and a decreased hERG selectivity window. Similarly, although compounds 4 and 5 have comparable ROMK inhibitory potency and longer half-lives in rats as compared to 2 , they were less selective against hERG, raising concerns about the potential for QTc prolongation.…”

“…The observed improvements in half-life while maintaining ROMK inhibitory potency achieved by analogues 4 and 5 (Table ) prompted us to focus on searching for new head groups that could attach to the spirocyclic core and restore selectivity against hERG. Through extensive structure–activity relationship (SAR) studies of head groups by parallel synthesis, we found that, in general, the most-potent pharmacophores contained heterocycles with or without attached heteroatoms or nitrile groups. , Unfortunately, compounds with these head groups usually displayed poor-to-moderate hERG selectivity. Compound 2 , bearing two lactone-containing head groups, had proven to be one of the most ROMK potent and hERG selective ROMK inhibitors to date.…”

Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors

“…The first reported selective, small-molecule ROMK inhibitor VU591 ( 1 , Figure ) was demonstrated to inhibit potassium transport in isolated perfused rat collecting duct tubules with no effect on sodium transport . Since this initial report, several disclosures by investigators at Merck − have established the in vivo efficacy of small-molecule ROMK inhibitors (Figure ), including Compound A ( 2 ) and clinical candidate MK-7145 ( 3 ), as powerful diuretic and natriuretic agents that, in contrast to thiazides and loop diuretics, have minimal impact on kaliuresis. − A number of small-molecule ROMK inhibitors have also been disclosed in the patent literature …”