Darigabat (developmental code names CVL-865, PF-06372865, PF-6372865) is a

GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter gamma-aminobutyric acid (GABA). For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic ...

medication which is under development for the treatment of

photosensitive epilepsy Photosensitive epilepsy (PSE) is a form of epilepsy in which seizures are triggered by visual stimuli that form patterns in time or space, such as flashing lights, bold, regular patterns, or regular moving patterns. PSE affects approximately one ...

, focal onset seizures,

panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

, and other

anxiety disorder Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...

s. It was also under development for the treatment of

generalized anxiety disorder Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning. Individuals with GAD are often overly con ...

and chronic lower back pain, but development for these indications was discontinued. It is taken via

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Darigabat acts as a GABA_A receptor positive allosteric modulator It is specifically a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

that selectively targets α₂, α₃, and α₅ subunit-containing GABA_A receptors, with minimal

functional activity An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

at α₁ subunit-containing GABA_A receptors. A dose of darigabat that achieved more than 80% receptor occupancy showed no

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

with

dose titration Drug titration is the process of adjusting the dose of a medication for the maximum benefit without adverse effects. When a drug has a narrow therapeutic index, titration is especially important, because the range between the dose at which a drug ...

, whereas

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s, which are non-selective GABA_A receptor positive allosteric modulators, achieve only 10 to 15% receptor occupancy whilst producing significant or severe somnolence. It is theorized that α₁ subunit-containing GABA_A receptors preferentially mediate

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

amnesia Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

, and

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, whereas α₂ and α₃ subunit-containing GABA_A receptors mediate

anxiolysis An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

. However, this model has also been questioned. α₁ subunit-containing GABA_A receptors are said to be completely unaffected by darigabat. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of darigabat is 11hours and it is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

mainly by

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

. In clinical trials conducted thus far,

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of darigabat have included

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, mild-to-moderate

bradyphrenia Bradyphrenia is the slowness of thought common to many disorders of the brain. Disorders characterized by bradyphrenia include Parkinson's disease and forms of schizophrenia consequently causing a delayed response and fatigue. Patients with brady ...

(slowness of thought), modest

memory impairment Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

, mild

cognitive impairment Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...

, balance impairment, and feeling abnormal. It has been described as well-tolerated. Darigabat was originated by

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

and is under development by

Cerevel Therapeutics Cerevel Therapeutics Holdings, Inc. was an American biotechnology and pharmaceuticals company based in Cambridge, Massachusetts, focused on the development of novel therapies for mental and neurological illnesses. History Cerevel was establish ...

and

. As of January 2023, it is in

phase 2 Michael Lawrence Marrow (August 2, 1955 – December 12, 2019), known as PHASE 2 and Lonny Wood, was an American aerosol paint artist based in New York City. Mostly active in the 1970s, Phase 2 is generally credited with originating the "bubble ...

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for epilepsy and seizures, phase 1 trials for panic disorder, and

preclinical development In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

for anxiety disorders. Development for back pain was discontinued due to lack of effectiveness in a phase 2 trial, while development for generalized anxiety disorder was discontinued due to business reasons as well as lack of effectiveness in a phase 2 trial.

References

External links

Darigabat - AdisInsight
{{GABAA receptor positive allosteric modulators Experimental anxiolytics Experimental drugs Anticonvulsants Anxiolytics GABAA receptor positive allosteric modulators Fluoroarenes Imidazopyridazines Methoxy compounds Phenyl compounds Pyridazines Sulfones

See also

References

External links