Omecamtiv Mecarbil Salt Forms for Stable Calcium-Independent Therapy
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Solution Overview
Problem
There is a need for various new salt and crystalline forms of omecamtiv mecarbil with different chemical and physical stabilities, and formulations to address the limitations of current positive inotropic agents that increase intracellular calcium levels, leading to potentially life-threatening side effects.
Innovation Solution
Development of salts and crystal forms of omecamtiv mecarbil, including free base crystalline forms and crystalline salts such as hydrochloride, fumarate, maleate, and sulfate salts, which provide enhanced chemical and physical stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If current positive inotropic agents (beta-adrenergic receptor agonists or phosphodiesterase inhibitors) are used to increase intracellular calcium concentration, then cardiac sarcomere contractility is improved, but the velocity of cardiac muscle contraction increases and systolic ejection time is shortened, leading to potentially life-threatening side effects
Solution Approach 1:
The patent changes the mechanism of action from calcium concentration increase to direct myosin activation. Omecamtiv mecarbil binds to the myosin motor protein and stabilizes the force-producing state, increasing contractility without increasing calcium levels or contraction velocity, thereby avoiding the harmful side effects associated with rapid contraction
Solution Approach 2:
The patent introduces omecamtiv mecarbil as an intermediary substance that directly activates myosin. This intermediary binds to the myosin motor protein and shifts the enzymatic cycle toward the force-producing state, serving as a mediator between calcium-free conditions and effective contraction, thus avoiding the harmful effects of calcium-mediated contraction
2Stability of the object's composition
If omecamtiv mecarbil is formulated in multiple salt and crystal forms, then chemical and physical stability is improved for pharmaceutical formulations, but device complexity and manufacturing complexity increase
Solution Approach 1:
The patent segments the active ingredient into multiple salt forms and crystal forms (free base, hydrochloride, ethane sulfonate, bis-fumarate, bis-maleate, etc.). Each form has distinct stability characteristics and can be selected or combined based on specific formulation requirements, allowing optimization of chemical and physical stability for different pharmaceutical applications
Solution Approach 2:
The patent changes the physical and chemical parameters of omecamtiv mecarbil by creating different salt forms and crystal forms. Each form has different solubility, stability, and pharmacokinetic properties, allowing the formulation to be optimized for specific therapeutic needs while maintaining the core active ingredient
Data Source
AI summary
Provided herein are free base crystalline forms, crystalline salts, and an amorphous salts of omecamtiv mecarbil.