Piperidine urea derivatives for use as inotropic agents
Inventors
Lund, Lars • Bernareggi, Alberto • Lovati, Emanuela • Giuliano, Claudio • Pietra, Claudio
Assignees
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Publication Number
US-12569476-B2
Publication Date
2026-03-10
Expiration Date
Abstract
The invention concerns the use of compounds represented by formula (I) as inotropic agents. The compounds of formula (I), which include, as preferred, 1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-methyl-3,3-dimethyl-4-piperidyl]-urea and its hydrochloride salt, are herein reported to have a significant inotropic activity on cardiomyocytes from both normal and myocardial infarction-induced heart failure animal models, which makes them useful for treating cardiovascular patients in need thereof. Differently from known inotropic agents, the present compounds are effective on cardiomyocyte contractility without influencing calcium mobilization. Accordingly, they are advantageously free from adverse effects caused by increased calcium concentrations, such as increased oxygen demand, tachycardia, arrhythmia, ischemia, etc. Overall, a new, safe and effective inotropic treatment is thus made available.
Core Innovation
The invention relates to piperidine urea derivatives of formula I as ghrelin-receptor-mediated inotropic agents for treating heart failure with reduced ejection fraction. A preferred stereospecific compound is described as AC01/HM01, including its hydrochloride salt (monohydrochloride). The document presents these compounds as a pharmaceutical approach that acts through ghrelin receptor mechanisms to produce positive inotropy.
The problem addressed is the occurrence of calcium-related adverse effects in heart failure therapies that increase calcium concentration, including increased myocardial oxygen demand, tachycardia, arrhythmia, ischemia, and hypotension. The described pharmacological intent is to provide positive inotropy without increasing calcium transient amplitude or calcium mobilization, thereby aiming to reduce calcium-associated risks.
The document reports that the compounds increase contractility in cardiomyocytes by enhancing sarcomere sensitivity to existing Ca2+ rather than increasing Ca2+ transient amplitude. Preclinical results in a mouse myocardial-infarction heart failure model and in SHAM cardiomyocytes show dose-dependent increased fractional shortening that is blocked by the ghrelin antagonist D-Lys3-GHRP-6, along with unchanged Ca2+ transients. The document further reports reduced cTnI (Ser22/23) phosphorylation, reduced protein kinase A (PKA) activity, and proposes Gαi-linked signaling.
Claims Coverage
The partial claim set includes one independent claim and multiple dependent claims. The inventive coverage focuses on administering a compound having the specified structure (or a pharmaceutically acceptable salt) to treat heart failure with reduced ejection fraction, with dependent claims refining patient severity, salt form, and side-effect avoidance tied to increased calcium concentration.
Treating heart failure with reduced ejection fraction by administering a specified compound
A method of treating heart failure with reduced ejection fraction in a patient in need thereof, comprising administering a compound having the structure or a pharmaceutically acceptable salt thereof to the patient.
Avoiding side effects caused by increased calcium concentration
The method wherein the administration avoids side effects caused by increased calcium concentration after administering the compound or pharmaceutically acceptable salt.
Using a monohydrochloride pharmaceutically acceptable salt
The method wherein the pharmaceutically acceptable salt is a monohydrochloride salt.
Treating severe, advanced, or chronic heart failure with reduced ejection
The method wherein the heart failure with reduced ejection is severe, advanced, or chronic.
Treating acute heart failure with reduced ejection
The method wherein the heart failure with reduced ejection is acute heart failure.
Selecting side effects associated with increased calcium concentrations
The method wherein side effects attributed to increased calcium concentrations are selected from increased myocardial oxygen demand, ischemia, arrhythmia, and hypotension.
Overall, the claim coverage centers on using the specified piperidine urea derivative structure (or a pharmaceutically acceptable salt) for treating heart failure with reduced ejection fraction, with refinements to a monohydrochloride salt form, to severity (severe/advanced/chronic or acute), and to avoidance/selection of adverse outcomes associated with increased calcium concentration.
Stated Advantages
Positive inotropy is achieved without increasing calcium transient amplitude or calcium mobilization.
Dose-dependent increased fractional shortening is observed.
Increased fractional shortening is blocked by the ghrelin antagonist D-Lys3-GHRP-6.
Reduction of cTnI (Ser22/23) phosphorylation and reduced PKA activity are reported.
The approach is intended to avoid calcium-associated adverse effects including increased myocardial oxygen demand, ischemia, arrhythmia, and hypotension.
Documented Applications
Preclinical evaluation in a mouse myocardial-infarction heart failure model (MI/HF) and in SHAM cardiomyocytes, assessing fractional shortening and calcium-related readouts.
Phase 1 SAD study in healthy males using HM01 HCl, reporting PK parameters (including parent and metabolites) and PD/hormone changes, and recording TEAEs such as dose-dependent sinus bradycardia and headache.
Phase 1b/2a randomized placebo-controlled multiple ascending dose trial in HFrEF patients to assess safety, PK/PD, and exploratory efficacy/hemodynamics (including measures such as echocardiography, cardiac output, stroke volume, and ECG-related assessments).
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