Delving into the Latest Updates on ABT-288 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ABT 288

Target

H3 receptor

Action

antagonists

Mechanism

H3 receptor antagonists(Histamine H3 receptor antagonists)

Therapeutic Areas

Nervous System DiseasesCongenital DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication-

Inactive Indication

Alzheimer DiseaseChanarin-Dorfman SyndromeCognitive Dysfunction+ [1]

Originator Organization

AbbVie, Inc.

Active Organization-

Inactive Organization

AbbVie, Inc.

License Organization-

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H24N4O

InChIKeyGNIRITULTPTAQW-KNQAVFIVSA-N

CAS Registry948845-91-8

In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.

01 Oct 2015·Journal of Alzheimer's disease : JADQ3 · MEDICINE

Histamine H3 Receptor Antagonists for Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

Q3 · MEDICINE

Review

Author: Kubo, Momoko ; Kishi, Taro ; Iwata, Nakao ; Matsunaga, Shinji

BACKGROUND:

No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of histamine H3 receptor antagonists (H3R-ANTs) in Alzheimer's disease patients.

OBJECTIVE:

We performed a systematic review and meta-analysis of double-blind randomized placebo-controlled trials (RCTs) of H3R-ANTs for Alzheimer's disease.

METHODS:

Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to June 19, 2015. The primary outcome was a change in the Mini-Mental State Examination (MMSE) scores. Secondary outcomes were Neuropsychiatric Inventory (NPI) scores, discontinuation rate, and individual adverse events/side effects. Risk ratios, numbers-needed-to-treat/harm, and standardized mean differences were calculated based on a random effects model.

RESULTS:

The computerized search initially yielded 33 studies after excluding duplicates. We excluded 29 of these articles following a review of titles and abstracts and one RCT including healthy subjects after full-text review. We identified three RCTs (two on GSK239512 and one on ABT-288) including 402 patients. Pooled H3R-ANTs were not superior to placebo for improvement in MMSE and NPI scores. Discontinuation rate and individual adverse events/side effects did not differ among the pooled groups.

CONCLUSIONS:

Our results suggest that H3R-ANTs are not effective in treating cognitive dysfunction in Alzheimer's disease. However, further studies with larger samples are required for definitive conclusions regarding responsive subpopulations.

01 Nov 2014·Schizophrenia bulletinQ1 · MEDICINE

A Randomized Trial of the Efficacy and Safety of the H3 Antagonist ABT-288 in Cognitive Impairment Associated With Schizophrenia

Q1 · MEDICINE

Article

Author: Haig, George M ; Baker, Jeffrey ; Lenz, Robert A ; Bain, Earle ; Robieson, Weining ; Othman, Ahmed A

INTRODUCTION:

ABT-288 is a highly potent histamine-3 receptor antagonist that has demonstrated pro-cognitive effects in preclinical models relevant to schizophrenia. This study evaluated the efficacy and safety of two doses of ABT-288 in the treatment of cognitive impairment associated with schizophrenia.

METHODS:

A randomized, double-blind, placebo-controlled, parallel-group 12-week study was conducted at 23 centers in the United States. Clinically stable subjects with schizophrenia were randomized in an equal ratio to ABT-288 10 mg, ABT-288 25 mg, or placebo once daily while continuing their antipsychotic regimen. The primary efficacy measure was the change from baseline to day 84 evaluation on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) composite score vs placebo. Secondary measures included cognitive functioning and psychiatric scales. Safety assessments and sparse pharmacokinetic sampling were also conducted.

RESULTS:

A total of 214 subjects were randomized. The mean baseline MCCB composite score was 28.4. Approximately 80% of subjects completed the study. The MCCB composite score mean change from baseline to day 84 was numerically worse for both the 10 mg (1.90, P = .618) and 25 mg (0.64, P = .946) doses of ABT-288 vs placebo (2.19). Results from the secondary measures were consistent with the primary analysis. Subjects' schizophrenia symptoms remained stable throughout the study as evidenced by stable Positive and Negative Syndrome Scale scores. Overall, study medication was tolerated; however, an increased incidence of psychosis-related and sleep-related adverse events was associated with ABT-288.

DISCUSSION:

Neither dose of ABT-288 resulted in cognitive improvement in clinically stable adults with schizophrenia.

100 Deals associated with ABT-288

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15192

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chanarin-Dorfman Syndrome	Phase 2	United States	AbbVie, Inc.	01 Mar 2010
Cognitive Dysfunction	Phase 2	United States	AbbVie, Inc.	01 Mar 2010
Schizophrenia	Phase 2	United States	AbbVie, Inc.	01 Mar 2010
Alzheimer Disease	Phase 2	Russia	AbbVie, Inc.	01 Dec 2009
Alzheimer Disease	Phase 2	Ukraine	AbbVie, Inc.	01 Dec 2009