Ciraparantag

Chemical Nomenclature and Classification

This compound possesses a complex chemical structure that reflects its sophisticated design principles and functional requirements. The compound's International Union of Pure and Applied Chemistry name is (2S)-2-amino-N-[3-[4-[3-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]propyl]piperazin-1-yl]propyl]-5-(diaminomethylideneamino)pentanamide, which accurately describes its intricate molecular architecture. This systematic nomenclature reveals the presence of multiple functional groups that contribute to the molecule's binding capabilities and pharmacological properties.

The molecular formula C22H48N12O2 indicates a substantial nitrogen content, which is crucial for the compound's mechanism of action. With a molar mass of 512.708 grams per mole, this compound falls within the category of small molecules while maintaining sufficient complexity to achieve its desired binding characteristics. The compound is classified as an N-alkylpiperazine, reflecting the central piperazine ring structure that serves as the backbone for the molecule's functional domains.

The Chemical Abstracts Service registry number 1438492-26-2 provides a unique identifier for this compound in chemical databases and regulatory documentation. The compound is also known by several synonyms, including PER-977, which represents its original development designation, and aripazine, an alternative generic name. These various nomenclature forms reflect the compound's evolution through different stages of development and regulatory processes.

The structural characteristics of this compound reveal a carefully designed architecture consisting of two L-arginine groups connected by a short linking chain containing a piperazine moiety. This design enables the molecule to function as a synthetic water-soluble cationic entity capable of forming noncovalent hydrogen bonds and charge-charge interactions with target anticoagulants. The presence of multiple positively charged groups allows the molecule to interact effectively with the negatively charged regions of various anticoagulant compounds, forming stable but reversible complexes that neutralize their biological activity.

Historical Development Context

The development of this compound emerged from a strategic response to evolving challenges in anticoagulant therapy management, particularly following the introduction of direct oral anticoagulants in the early 2010s. Perosphere Inc., the original developer of the compound, initiated a systematic program of molecular design aimed at creating a broad-spectrum anticoagulant reversal agent. This development effort represented a significant departure from traditional approaches that typically focused on creating specific antidotes for individual anticoagulant classes.

The initial phase of development involved extensive computer modeling using energy minimization techniques to predict binding interactions between candidate molecules and various anticoagulant targets. Multiple structural hypotheses were evaluated, synthesized, and tested against fondaparinux, enoxaparin, and unfractionated heparin. The compound that would eventually become this compound demonstrated superior binding affinity compared to other candidates, leading to its selection for further development and optimization.

A pivotal moment in this compound's development occurred in April 2015 when the United States Food and Drug Administration granted fast-track designation for the compound as an investigational anticoagulant reversal agent. This designation recognized the significant unmet medical need for effective reversal agents in the era of direct oral anticoagulants and expedited the regulatory pathway for clinical development. The fast-track designation also reflected regulatory confidence in the compound's potential therapeutic value and its novel mechanism of action.

The corporate landscape surrounding this compound underwent significant changes during its development trajectory. In January 2019, AMAG Pharmaceuticals completed the acquisition of Perosphere Pharmaceuticals Inc., bringing this compound into a larger pharmaceutical development portfolio. This acquisition represented a strategic investment of approximately 40 million dollars in cash consideration, reflecting the perceived value of the compound and its development potential. The acquisition provided additional resources and infrastructure necessary for advancing this compound through late-stage clinical development.

The international expansion of this compound's development program materialized in July 2020 through an exclusive licensing agreement between AMAG Pharmaceuticals and Norgine B.V.. This collaboration encompassed development and commercialization rights for Europe, Australia, and New Zealand, with Norgine providing 30 million dollars in upfront consideration and committing to contribute one-third of Phase 3 clinical program costs. The partnership arrangement demonstrated international recognition of this compound's potential value and established a framework for global development and eventual commercialization.

Therapeutic Relevance and Research Significance

This compound's therapeutic significance stems from its unique position as a potential universal anticoagulant reversal agent capable of neutralizing multiple classes of anticoagulant medications through a single mechanism of action. The compound addresses a critical gap in clinical practice where healthcare providers frequently encounter patients receiving various anticoagulant therapies who require emergency reversal for life-threatening bleeding or urgent surgical interventions. Current estimates indicate approximately six million patients in the United States and nine million patients in other countries receive direct oral anticoagulant or low molecular weight heparin therapy, with approximately 1.5 to 2 percent experiencing serious bleeding complications annually.

The molecular mechanism underlying this compound's therapeutic effects involves direct noncovalent binding to anticoagulant molecules through charge-charge interactions and hydrogen bonding. This binding effectively removes anticoagulants from their intended target sites, allowing rapid reestablishment of normal blood coagulation processes. Unlike traditional reversal approaches that may require specific antidotes for different anticoagulant classes, this compound's broad-spectrum activity potentially simplifies emergency treatment protocols and reduces the complexity of maintaining multiple reversal agents in clinical settings.

Research investigations have demonstrated this compound's binding affinity for a comprehensive range of anticoagulant medications, including unfractionated heparin, low-molecular-weight heparin, fondaparinux, and direct oral anticoagulants such as rivaroxaban, apixaban, edoxaban, and dabigatran. Notably, the compound does not demonstrate significant binding to argatroban or vitamin K antagonists, indicating specificity in its target recognition. Dynamic light-scattering methodology has confirmed physical, noncovalent binding between this compound and evaluated anticoagulants while demonstrating lack of binding to various proteins including coagulation factors and commonly used medications.

The pharmacokinetic profile of this compound supports its potential clinical utility, with the compound reaching maximum concentration within minutes after intravenous administration and maintaining a half-life of 12 to 19 minutes. The compound undergoes hydrolysis by serum peptidases into two metabolites, neither of which demonstrates substantial anticoagulant activity. Both this compound and its metabolites are recovered almost entirely in urine, suggesting a predictable elimination pathway that minimizes potential for drug accumulation or prolonged effects.

Preclinical research has provided compelling evidence for this compound's therapeutic potential through animal bleeding models that demonstrate significant reduction in blood loss across various anticoagulant scenarios. In rat tail transection models, single intravenous doses of this compound administered at peak anticoagulant concentrations significantly reduced blood loss when given both before and after bleeding injuries. Similar efficacy was observed in liver laceration models, where this compound at specified doses reduced bleeding time in edoxaban-treated animals. These preclinical findings support the compound's potential to improve clinical outcomes in emergency bleeding situations.

The research significance of this compound extends beyond its immediate therapeutic applications to encompass broader implications for anticoagulant therapy management and emergency medicine protocols. The development of a universal reversal agent could fundamentally alter clinical decision-making processes by providing healthcare providers with confidence that effective reversal options exist for patients receiving any of the commonly used anticoagulant medications. This assurance may facilitate more appropriate anticoagulant prescribing decisions and potentially improve patient outcomes through reduced hesitation to initiate necessary anticoagulant therapy due to reversal concerns.

Human clinical research has demonstrated this compound's ability to achieve complete reversal of anticoagulation within 10 minutes of administration, with effects sustained for up to 24 hours. These findings represent significant advances in reversal agent development, as the rapid onset and sustained duration of action address critical clinical needs for immediate hemostatic restoration and prolonged protection against rebound anticoagulant effects. The compound's performance in human volunteer studies has established proof-of-concept for its therapeutic mechanism and supported advancement to more extensive clinical development programs.