Remimazolam API Manufacturers

General Description:

Remimazolam, identified by CAS number 308242-62-8, is a notable compound with significant therapeutic applications. Remimazolam is an ultra short-acting benzodiazepine used in the induction and maintenance of sedation during short (<30 minute) procedures. Recent trends in anesthesia-related drug development have touted the benefits of so-called "soft drugs" - these agents, such as , are designed to be metabolically fragile and thus susceptible to rapid biotransformation and elimination as inactive metabolites. These "soft drugs" are useful in the context of surgical procedures, wherein a rapid onset/offset is desirable, enabling anesthesiologists to manipulate drug concentrations as needed. Remimazolam was the first "soft" benzodiazepine analog to be developed and was approved for use by the FDA in July 2020 under the brand name Byfavo.

Indications:

This drug is primarily indicated for: Remimazolam is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Remimazolam undergoes metabolic processing primarily in: Remimazolam does not appear to undergo biotransformation via hepatic cytochrome P450 enzymes, nor does it induce or inhibit these enzymes. Its primary route of metabolism is hydrolysis via hepatic carboxylesterase-1 (CES1) to yield the inactive CNS7054 metabolite, which then undergoes glucuronidation and hydroxylation prior to elimination. CNS7054 possesses a 300-fold lesser affinity for GABA(A) receptors as compared to the parent drug. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Remimazolam are crucial for its therapeutic efficacy: The C_max and AUC_0-inf following intravenous administration of 0.01 to 0.5 mg/kg were 189 to 6,960 ng/mL and 12.1 to 452 ng∙h/mL, respectively, and appear to be relatively dose proportional. The T_max of the inactive CNS7054 metabolite is approximately 20-30 minutes and its AUC_0-inf ranges from 231 to 7,090 ng∙h/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Remimazolam is an important consideration for its dosing schedule: Following intravenous administration, the distribution half-life is of remimazolam is 0.5 - 2 minutes and the terminal elimination half-life is 37 - 53 minutes. Half-life is increased in patients with hepatic impairment necessitating careful dose titration in this population. The half-life of remimazolam's major inactive metabolite, CNS7054, is 2.4 - 3.8 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Remimazolam exhibits a strong affinity for binding with plasma proteins: Remimazolam is >91% protein-bound in plasma, primarily to serum albumin. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Remimazolam from the body primarily occurs through: In patients undergoing colonoscopy, approximately 0.003% of the administered dose is excreted in the urine as unchanged parent drug and 50-60% is excreted in the urine as CNS7054. In healthy subjects, >80% of the administered dose is excreted in the urine as CNS7054. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Remimazolam is distributed throughout the body with a volume of distribution of: The volume of distribution is approximately 0.76 - 0.98 L/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Remimazolam is a critical factor in determining its safe and effective dosage: The clearance of remimazolam is approximately 24 - 75 L/h and is independent of body weight. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Remimazolam exerts its therapeutic effects through: Remimazolam modulates the effects of GABA(A) receptors in order to enhance the effects of GABA. It is considered an "ultra short-acting" benzodiazepine that achieves peak sedation within 3 to 3.5 minutes following intravenous administration, a property that makes it desirable for use during short procedures. Hepatic impairment can result in elevated serum levels of remimazolam - patients with severe hepatic impairment should be carefully titrated to effect. As of its approval date, remimazolam has not received a scheduling action by the DEA under the Controlled Substances Act. As benzodiazepines as a class have been implicated in the development of drug dependence and have a known potential for abuse, remimazolam should be used with caution in patients with a history of drug dependence or abuse. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Remimazolam functions by: Like other benzodiazepines, remimazolam exerts its therapeutic effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA(A) receptors, the main inhibitory neurotransmitter receptors in the mammalian brain. GABA(A) receptors are a component of GABA-gated ionotropic chloride channels that produce inhibitory postsynaptic potentials - following activation by GABA, the channel undergoes a conformational change that allows the passage of chloride ions through the channel. The inhibitory potentials produced by GABA neurotransmission play an integral role in the suppression and control of epileptiform nerve firing such as that seen in epilepsy, which makes the GABA system a desirable target in the treatment of epilepsy. Benzodiazepines are positive allosteric modulators of GABA(A) function. They bind to the interface between alpha (α) and gamma (γ) subunits on the receptor, commonly referred to as the benzodiazepine binding site, and modulate the receptor such that its inhibitory response to GABA binding is dramatically increased. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Remimazolam belongs to the class of organic compounds known as 1,4-benzodiazepines. These are organic compounds containing a benzene ring fused to a 1,4-azepine, classified under the direct parent group 1,4-benzodiazepines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Benzodiazepines class, specifically within the 1,4-benzodiazepines subclass.

Categories:

Remimazolam is categorized under the following therapeutic classes: Benzazepines, Benzodiazepine hypnotics and sedatives, Benzodiazepines and benzodiazepine derivatives, Central Nervous System Depressants, GABA Agents, GABA Modulators, Heterocyclic Compounds, Fused-Ring, Hypnotics and Sedatives, Nervous System, Psycholeptics, Tranquilizing Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Remimazolam include:

• Water Solubility: Sparingly soluble