Delving into the Latest Updates on Ocinaplon with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Ocinaplon (USAN/INN), CL 273547, CL-273547

+ [1]

Target

GABAA receptor

Mechanism

GABAA receptor modulators(Gamma-aminobutyric acid A receptor modulators)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Anxiety Disorders

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Euthymics Bioscience, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC17H11N5O

InChIKeyOQJFBUOFGHPMSR-UHFFFAOYSA-N

CAS Registry96604-21-6

Anxiety disorders are the most prevalent psychiatric pathology with substantial cost to society, but the existing treatments are often inadequate. This has rekindled the interest in the GABA_A-receptor (GABA_AR) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam. While the GABA_AR PAMs possess remarkable anxiolytic efficacy, they have fallen out of favor due to a host of adverse effects including sedation, motor impairment, addictive potential and tolerance development. A substantial effort was thus devoted to the design of GABA_AR PAMs as anxiolytics with reduced sedative liabilities. Several non-benzodiazepine (BZD) GABA_APAMs progressed to clinical trials (bretazenil, abecarnil, alpidem, and ocinaplon) with alpidem obtaining regulatory approval as anxiolytic, but later withdrawn from market due to hepatotoxicity. Advances in molecular biology gave birth to a host of subtype selective GABA_AR-PAMs which suffered from signs of sedation and motor impairment and only three compounds progressed to proof-of-concept studies (TPA-023, AZD7325 and PF-06372865). TPA-023 was terminated due to toxicity in preclinical species while AZD7325 and PF-06372865 did not achieve efficacy endpoints in patients. We highlight a new compound, KRM-II-81, that is an imidazodiazepine selective for GABA_AR containing α2/3 and β3 proteins. In preclinical studies KRM-II-81 produced anxiolytic-like effects but with minimal sedation, respiratory depression, and abuse liability. Thus, KRM-II-81 is a newly discovered, non- BZD anxiolytic compound, which targets a selective population of GABA_AR for improved therapeutic gain and reduced side effects.

01 Nov 2022·Medicinal ChemistryQ4 · MEDICINE

New Route to the Synthesis of Novel Pyrazolo[1,5-a]pyrimidines and Evaluation of their Antimicrobial Activity as RNA Polymerase Inhibitors

Q4 · MEDICINE

Article

Author: Elgemeie, Galal H. ; Abdallah, Amira E. M.

Aims::

The current study aimed to synthesize novel pyrazolo[1,5-a]pyrimidines based on 5- aminopyrazoles 3, evaluate their antimicrobial activity, and study the minimum inhibitory concentration (MIC) for the most active compounds. In addition, molecular docking studies and RNA polymerase inhibitory activity were determined.

Background::

Starting with our previously reported 5-aminopyrazoles 3, a number of novel pyrazolo[1,5- a]pyrimidines were synthesized. Due to the similarity of pyrazolopyrimidine derivatives with the purine systems, pyrazolopyrimidines are important in many different biological applications, most notably as anti-tumor, antibacterial, and hepatitis C virus inhibitors. The pharmaceutical applications of the pyrazolopyrimidine derivatives were explained in several approved drugs like Indiplon, Zaloplan, and Ocinaplon.

Objective::

To prepare a novel antimicrobial agent, namely pyrazolo[1,5-a]pyrimidine, reveal their structures using different spectral data, the minimum inhibitory concentration (MIC) for the most active compounds was evaluated, and both the molecular docking and the RNA polymerase inhibitory activity were determined.

Methods::

A number of different pyrazolopyrimidines namely 2-(phenylamino)-6,11-dihydrobenzo[g]pyrazolo [1,5-a]quinazoline-3-carboxamides (5a-c), (E)-5,7-dimethyl-2-(phenylamino)-6-(phenyldiazenyl)pyrazolo-[1,5- a]pyrimidine-3-carboxamides (7a-c), 7-amino-2-(phenylamino) pyrazolo[1,5-a]pyrimidine-3-carboxamides (11af), 7-amino-2-(phenylamino)-5-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carboxamides (14-f) and ethyl 7-amino-3- carbamoyl-2-(phenylamino)-5-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate derivatives (14g-i) were synthesized through the reaction of 5-aminopyrazoles 3 with a variety of chemical reagents. On the other hand, the evaluation of the antimicrobial activity for all the prepared compounds was screened through different strains as Gram-positive bacteria, such as staphylococcus aureus and Streptococcus mutans, and Gram-negative bacteria, such as Escherichia coli, Pseudomonas aeruginosa, and klebsiella. The antifungal activity was determined by Candids Albicans fungal strain, and the MIC of the most active compounds was measured. The molecular docking was recorded, and the RNA polymerase inhibitory activity was estimated for the high docking score compounds.

Results::

Compounds 5a, 5b, 5c, 7a, 7b, 7c, 11d, 14b, and 14h were the most active compounds against some of the bacterial and fungal tested strains. MIC was determined for the most active tested compounds. As an antimicrobial agent, compound 7b was the most potent, with a high docking score and RNA polymerase inhibitory activity (IC50= 0.213 μg/ml) compared to Rifampicin (IC50= 0.244 μg/ml). The reactivity of the latter compound was attributed to the presence of 4-Br-C6H4 moiety. The results demonstrated that docking studies on the most active compounds in the RNA polymerase active site were consistent with in vitro assays.

Conclusion::

The resultant novel bioactive pyrazolo[1,5-a]pyrimidine derivatives were synthesized based on 5- aminopyrazole derivatives 3. The current study evaluated the antimicrobial activity for all the prepared compounds, followed by the determination of the MIC for the most potent active compounds. The molecular docking study was performed, and it was appropriate with the in vitro activity. The RNA polymerase inhibitory activity was assessed for the most active antimicrobial compounds with a high docking score (7b, 7c, 14a, 14b, 14e, 14i). Compound 7b was the most potent compound inhibiting RNA polymerase enzyme compared to the reference drug Rifampicin.

Other::

The novel prepared heterocyclic systems are extremely important in a variety of domains, especially biological and pharmacological ones.

01 Mar 2013·Trends in pharmacological sciencesQ1 · MEDICINE

Anxioselective anxiolytics: additional perspective

Q1 · MEDICINE

Letter

Author: Werner Sieghart

A review.This article discusses the importance of anxioselective anxiolytics.It is noted that the relative strength of activation of the various receptor subtypes might be significant for the overall behavioral effects of drugs.Alpidem or ocinaplon might show the optimal ratio of stimulation of different GABA_A receptor subtypes for provoking anxiolysis in humans and mice.Addnl. studies should be conducted to elucidate whether ocinaplon and alpidem mediate their pos. allosteric action at GABA_A receptors exclusively through the BZ site or addnl. act via another binding site leading to decreased effects at β1-containing receptors.

100 Deals associated with Ocinaplon

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External Link

KEGG	Wiki	ATC	Drug Bank
D02617	Ocinaplon	-	DB06529

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Phase 3	US	-	-
Anxiety Disorders	Phase 3	-	Pfizer Inc.	-
Anxiety Disorders	Phase 3	-	Euthymics Bioscience, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


SFN2003	Not Applicable	Anxiety Disorders	-	Ocinaplon TID60mg	qwnkwrzrjq(dikhrynabf) = cyjlytaplx gomrgkrzgu (deabwyagsd )	-	12 Nov 2003
				Ocinaplon BID120mg	qwnkwrzrjq(dikhrynabf) = tdxcfrcaus gomrgkrzgu (deabwyagsd )