Delving into the Latest Updates on MK-7145 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

MK 7145

Target

KCNJ1

Action

inhibitors

Mechanism

KCNJ1 inhibitors(potassium inwardly rectifying channel subfamily J member 1 inhibitors)

Therapeutic Areas

Cardiovascular DiseasesUrogenital Diseases

Active Indication-

Inactive Indication

Essential HypertensionHeart FailureRenal Insufficiency

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.

License Organization-

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC26H30N2O6

InChIKeyOCKGFTQIICXDQW-ZEQRLZLVSA-N

CAS Registry1255204-84-2

Part I is a 3-period, active comparator-controlled, fixed sequence study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of MK-7145 compared to furosemide in participants with moderate-to-severe renal insufficiency (RI) without heart failure (HF). Primary hypothesis for Part I is that at least one well-tolerated dose of MK-7145 will produce a greater 24hr urinary excretion of sodium (UNa) on the 1st day of MK-7145 dosing than 80 mg furosemide (on the 1st day of furosemide dosing) in participants with moderate-to-severe RI. If MK-7145 is safe at natriuretic doses in RI in Part I of this study, MK-7145 will be investigated in participants with heart failure (HF) and RI (Part II).
Part II is 4 period, fixed sequence, active comparator controlled (in Period 1), titration (in Periods 2, 3 and 4) study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a titration regimen of MK-7145 compared to an optimized stable maintenance regimen of furosemide or torsemide in participants with New York Heart Association (NYHA) Class II and III heart failure and moderate or severe renal insufficiency. The primary hypothesis for Part II is that at least one dose of MK-7145, titrated according to a fixed dose titration regimen, will be associated with a reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) compared to furosemide or torsemide (at 24 hours post morning dose on the last dosing day of each period) in participants with NYHA class II/III HF with moderate or severe RI.

Start Date23 May 2014

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT01832103

/ WithdrawnPhase 1

A Phase I Study to Evaluate the Pharmacokinetics of MK-7145 Following Single Dose Administration in Patients With Moderate Renal Insufficiency

The primary purpose of this study is to obtain a preliminary pharmacokinetic profile of MK-7145 2 mg immediate release (IR) following single-dose administration in male participants with moderate renal insufficiency. In addition, the study will evaluate the pharmacodynamic effect of a single dose of MK-7145 2 mg IR on 24-hour net natriuresis in male participants with moderate renal insufficiency.

Start Date01 Aug 2013

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT01370655

/ CompletedPhase 1

A Phase Ib, Randomized, Double-Blind, 4-Treatment, 2-Period Incomplete Block Study to Evaluate the Multiple Dose Effects of MK-7145 and Hydrochlorothiazide Compared to Placebo on Blood Pressure in Male Patients With Hypertension

This study is being done to evaluate the antihypertensive efficacy and tolerability of MK-7145 in participants with mild-to-moderate hypertension.
The primary hypotheses for the study were as follows:
1. Multiple dose administration of 6-mg MK-7145 results in a reduction in systolic blood pressure (SBP) in male participants with mild to moderate hypertension that is superior to placebo, as measured by time weighted average change from baseline over 24 hours postdose (TWA0-24hrs) on dosing Day 28
2. Multiple dose administration of 6-mg MK-7145 results in a reduction in SBP in male participants with mild to moderate hypertension that is similar to hydrochlorothiazide (HCTZ), as measured by TWA0-24hrs on dosing Day 28
3. The effect of MK-7145 and HCTZ on natriuresis (UNaV) as well as SBP and diastolic blood pressure (DBP), both as measured by TWA0-24hrs, will be estimated
4. Multiple dose administration of MK-7145 for 4 weeks will be generally safe and well-tolerated.

Start Date15 Jun 2011

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with MK-7145

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100 Translational Medicine associated with MK-7145

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100 Patents (Medical) associated with MK-7145

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7

Literatures (Medical) associated with MK-7145

10 Jun 2021·Journal of medicinal chemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Chobanian, Harry R. ; Thomas-Fowlkes, Brande ; Jiang, Jinlong ; Bateman, Thomas J. ; Parmee, Emma R. ; Hu, Mengwei ; Pasternak, Alexander ; Hampton, Caryn ; Gibson, Jack ; Cutarelli, Timothy ; Sullivan, Kathleen ; Davies, Ian ; Weinglass, Adam ; Koehler, Martin ; Zhou, Xiaoyan ; Ding, Fa-Xiang ; Pio, Barbara ; Pai, Lee-Yuh ; Levorse, Dorothy ; Samuel, Koppara ; Gu, Xin ; Houle, Kevin ; Tang, Haifeng ; Dong, Shuzhi ; Keh deJesus, Reynalda ; Yudkovitz, Joel ; Margulis, Michael

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.

08 Feb 2018·ACS medicinal chemistry lettersQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Carpino, Philip A. ; Dowling, Matthew S. ; Kharade, Sujay V. ; Fernando, Dilinie P. ; Castle, Neil A. ; Carlo, Anthony ; Antonio, Brett M. ; Filipski, Kevin J. ; Boehm, Markus ; Gosset, James R. ; Smith, Aaron C. ; Zellmer, Shannon G. ; Sammons, Matthew F. ; Denton, Jerod S. ; Shavnya, Andre

Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4, this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors.

01 Oct 2017·Future medicinal chemistryQ4 · MEDICINE

The Therapeutic Potential of Targeting the K _Ir 1.1 (Renal Outer Medullary K ⁺ ) Channel

Q4 · MEDICINE

Review

Author: Pasternak, Alexander ; Priest, Birgit T

K_ir1.1 (renal outer medullary K⁺) channels are potassium channels expressed almost exclusively in the kidney and play a role in the body's electrolyte and water balance. Potassium efflux through K_ir1.1 compliments the role of transporters and sodium channels that are the targets of known diuretics. Consequently, loss-of-function mutations in men and rodents are associated with salt wasting and low blood pressure. On this basis, K_ir1.1 inhibitors may have value in the treatment of hypertension and heart failure. Efforts to develop small molecule K_ir1.1 inhibitors produced MK-7145, which entered into clinical trials. The present manuscript describes the structure-activity relationships associated with this scaffold alongside other preclinical K_ir1.1 blockers.

100 Deals associated with MK-7145

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11968

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Phase 1	-	Merck Sharp & Dohme Corp.	23 May 2014
Renal Insufficiency	Phase 1	-	Merck Sharp & Dohme Corp.	01 Aug 2013
Essential Hypertension	Phase 1	-	Merck Sharp & Dohme Corp.	15 Jun 2011