Indiplon in the management of insomnia

Abstract

Indiplon is a novel pyrazolopyrimidine, nonbenzodiazepine γ-aminobutyric acid (GABA) agonist studied for the treatment of insomnia. This article reviews the chemistry, pharmacology, clinical pharmacokinetics, drug interactions, clinical trials, safety, tolerability, contraindications, use in special populations, and dosing of indiplon. OVID, International Pharmaceutical Abstracts (IPA), and PubMed databases were searched (1966 to February 2009) for the keywords indiplon, NBI-34060, and insomnia. References of key articles were also reviewed to identify additional publications. Only English language articles were selected for review. Indiplon has been shown to have high affinity and selectivity for the GABAα1 receptor subunit associated with sedation. In clinical studies, indiplon has demonstrated efficacy in improving latency to sleep onset, latency to persistent sleep, total sleep time, wake time after sleep onset, number of awakenings after sleep onset, and overall sleep quality when compared to placebo. Indiplon has a favorable safety profile with limited rebound insomnia and no tolerance. Neurocrine Biosciences, Incorporated received an Approvable Letter from the United States Food and Drug Administration in December 2007 for the indiplon IR 5 mg and 10 mg capsules based on meeting three additional requirements. At the time of this writing, indiplon remains unapproved.

Synthesis of New GABAA Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold

“…Thus, the synthesis of 8-methoxy 3-(hetero)arylpyrazolo[1,5-a]quinazoline and 3-(hetero)aroylpyrazolo[1,5-a]quinazoline was planned. These compounds are most likely more metabolically stable then ester derivatives [18], and are structurally strictly related to compounds that have been claimed to be GABA A subtype receptor ligands such as Indiplon, Ocinaplon [4,19,20], and compounds of type I and II [21,22,23] (Figure 1, Panel A). All of these compounds belong to the pyrazolopyrimidines, triazolophtalazine, or pyrazolobenzotriazine family, whose core is easily recovered in our new synthesized PQ compounds (Figure 1, Panel B).…”

Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

“…Or Ph), different azido-aldehydes (R 1 = H, CF3, Br, Cl), and different maleimides (R 4 = Et, Me, Bn, Ph), which generates as a byproduct of only H2O and CO2. Among the pyrazolopyrimidines investigated as sedative-hypnotic agents, Indiplon [128] received an initial approval letter from the United States Food and Drug Administration (FDA). However, after further investigations, it remained unapproved unless more clinical studies are conducted.…”

“…These structures can be obtained in a one-step reaction as displayed in general Scheme 30, which allows a rapid synthesis of a variety of derivatives [131]. Among the pyrazolopyrimidines investigated as sedative-hypnotic agents, Indiplon [128] received an initial approval letter from the United States Food and Drug Administration (FDA). However, after further investigations, it remained unapproved unless more clinical studies are conducted.…”

A Simple and Easily Implemented Method for the Regioselective Introduction of Deuterium into Azolo[1,5-a]pyrimidines Molecules

“…Several drugs containing the pyrazolo[1,5- a ]pyrimidine backbone are used in medical practice. These include the sleeping pills Zaleplon [ 1 , 2 ], Indiplon and Lorediplon [ 3 , 4 ]; the sedative Ocinaplon [ 5 ]; the antifungal drug Pyrazophos [ 6 ]; the antiglycemic drug Anagliptin [ 7 , 8 ]; and the antitumor drug Dinaciclib [ 9 , 10 ] ( Figure 1 ). Moreover, an entire series of pyrazolo[1,5- a ]pyrimidine derivatives are registered, which have shown an antitumor effect [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], and effects on the central nervous system and serotonin receptors [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”