Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic.
Jinlong JiangFa-Xiang DingXiaoyan ZhouThomas J BatemanShuzhi DongXin GuReynalda Keh deJesusBarbara PioHaifeng TangHarry R ChobanianDorothy LevorseMengwei HuBrande Thomas-FowlkesMichael MargulisMartin KoehlerAdam WeinglassJack GibsonKevin HouleJoel YudkovitzCaryn HamptonLee-Yuh PaiKoppara SamuelTimothy CutarelliKathleen SullivanEmma R ParmeeIan DaviesAlexander PasternakPublished in: Journal of medicinal chemistry (2021)
A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.
Keyphrases
- blood pressure
- endothelial cells
- heart failure
- acute heart failure
- small molecule
- climate change
- healthcare
- high throughput
- induced pluripotent stem cells
- palliative care
- pluripotent stem cells
- heart rate
- stem cells
- type diabetes
- mesenchymal stem cells
- quality improvement
- skeletal muscle
- transcription factor
- atrial fibrillation
- metabolic syndrome
- anti inflammatory
- drug induced
- cardiac resynchronization therapy
- affordable care act
- weight loss
- electronic health record
- bone marrow