Part 1
To evaluate the pharmacokinetic (PK) profile of Arbaclofen Placarbil (AP) and R-baclofen following dosing of Arbaclofen Placarbil Modified Release (MR) Prototype A Tablet and Arbaclofen Placarbil MR Prototype B Tablet in healthy subjects
To determine the relative bioavailability of AP and R-baclofen following dosing of Arbaclofen Placarbil MR Prototype A Tablet and Arbaclofen Placarbil MR Prototype B Tablet compared to the reference Arbaclofen Placarbil Sustained Release (SR) Tablets (low dose)
To determine the relative bioavailability and PK of AP and R-baclofen following dosing of the selected MR prototype formulation(s) in the presence of beverage
To provide additional information on the safety and tolerability of single doses of AP
Part 2
To evaluate the PK profile of AP and R-baclofen following dosing of Arbaclofen Placarbil MR Prototype Tablets in healthy subjects
To determine the relative bioavailability and PK of AP and R-baclofen following dosing of Arbaclofen Placarbil MR Prototype Tablets compared to the reference Arbaclofen Placarbil Immediate Release (IR) Capsule
To provide additional information on the safety and tolerability of single doses of AP
To determine the relative bioavailability and PK of AP and R-baclofen following dosing of a selected MR prototype formulation in the fed state (optional)
To explore a possible in vitro in vivo correlation/relationship (IVIVC/IVIVR) for the Arbaclofen Placarbil MR Prototype Tablet Formulations
Part 3
To determine the relative bioavailability of the selected Arbaclofen Placarbil MR Prototype Tablet in the presence of either beverage or food and/or
To evaluate the PK profile (dose proportionality) of AP and R-baclofen following dosing of the selected Arbaclofen Placarbil MR Prototype A + B Tablet at different dose levels in healthy subjects
To provide additional information on the safety and tolerability of single doses of AP

Start Date24 Jan 2017

Sponsor / Collaborator

Indivior, Inc.

NCT02511886 / CompletedPhase 2

A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Determine the Maximum Tolerated Dose of Arbaclofen Placarbil in Subjects With Alcohol Use Disorder

This study will determine the maximum tolerated dose (MTD) of arbaclofen placarbil (AP) in the treatment of subjects with Alcohol Use Disorder (AUD). For every two subjects receiving AP, one subject will receive placebo.

Start Date01 Sep 2015

Sponsor / Collaborator

Indivior, Inc.

NCT01359566 / CompletedPhase 3

A Randomized, Double Blind, Placebo-Controlled Efficacy and Safety Study of Arbaclofen Placarbil in Subjects With Spasticity Due to Multiple Sclerosis

To evaluate the efficacy of three doses of XP19986 (arbaclofen placarbil) compared to placebo for the treatment of spasticity in subjects with multiple sclerosis (MS).

Start Date01 May 2011

Sponsor / Collaborator

XenoPort, Inc.

100 Clinical Results associated with Arbaclofen Placarbil

100 Translational Medicine associated with Arbaclofen Placarbil

100 Patents (Medical) associated with Arbaclofen Placarbil

Literatures (Medical) associated with Arbaclofen Placarbil

06 Aug 2024·Analytical Chemistry

Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper–Amino Acid Complexation and Ion Mobility-Mass Spectrometry

Article

Author: May, Jody C ; McLean, John A ; Blakley, Benjamin K ; Gupta, Rashi M ; Zlibut, Emanuel

Drug enantiomers can possess vastly different pharmacological properties, yet they are identical in their chemical composition and structural connectivity. Thus, resolving enantiomers poses a great challenge in the field of separation science. Enantiomer separations necessitate interaction of the analyte with a chiral environment─in mass spectrometry-based analysis, a common approach is through a three-point interaction with a chiral selector commonly introduced during sample preparation. In select cases, the structural difference imparted through noncovalent complexation results in enantiomer-specific structural differences, facilitating measurement using a structurally selective analytical technique such as ion mobility-mass spectrometry (IM-MS). In this work, we investigate the direct IM-MS differentiation of chiral drug compounds using mononuclear copper complexes incorporating an amino acid chiral selector. A panel of 20 chiral drugs and drug-like compounds were investigated for separation, and four l-amino acids (l-histidine, l-tryptophan, l-proline, and l-tyrosine) were evaluated as chiral selectors (CS) to provide the chiral environment necessary for differentiation. Enantiomer differentiation was achieved for four chiral molecule pairs (R/S-thalidomide, R/S-baclofen, R/S-metoprolol, and d/l-panthenol) with two-peak resolution (R_p-p) values ranging from 0.7 (>10% valley) to 1.5 (baseline separation). Calibration curves relating IM peak areas to enantiomeric concentrations enabled enantiomeric excess quantitation of racemic thalidomide and metoprolol with residuals of 5.7 and 2.5%, respectively. Theoretical models suggest that Cu^II and l-histidine complexation around the analyte chiral center is important for gas-phase stereoselectivity. This study demonstrates the potential of combining enantioselective noncovalent copper complexation with structurally selective IM-MS for differentiating chiral drugs and drug-like compounds.

30 Jul 2024·Journal of Alzheimer's Disease

Screening Targets and Therapeutic Drugs for Alzheimer’s Disease Based on Deep Learning Model and Molecular Docking

Article

Author: Zhong, Man-Li ; Li, Jia-Yi ; Gao, Hui-Ling ; Zhang, Ya-Hong ; Zhao, Pu

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder caused by a complex interplay of various factors. However, a satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it is paramount to search potential drug targets and drugs for AD. Objective: We aimed to provide novel targets and drugs for the treatment of AD employing transcriptomic data of AD and normal control brain tissues from a new perspective. Methods: Our study combined the use of a multi-layer perceptron (MLP) with differential expression analysis, variance assessment and molecular docking to screen targets and drugs for AD. Results: We identified the seven differentially expressed genes (DEGs) with the most significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, and WDR49) in transcriptomic data from AD brain. A newly built MLP was used to confirm the association between the seven DEGs and AD, establishing these DEGs as potential drug targets. Drug databases and molecular docking results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, and YC-1 had high affinity for GABBR2, and FABP3 bound with oleic, palmitic, and stearic acids. Arbaclofen and YC-1 activated GABAB receptor through PI3K/AKT and PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect and inhibiting p-tau and Aβ formation. Conclusions: This study provided a new strategy for the identification of targets and drugs for the treatment of AD using deep learning. Seven therapeutic targets and ten drugs were selected by using this method, providing new insight for AD treatment.

03 Jun 2024·Chemistry – An Asian Journal

Synthesis of R–GABA Derivatives via Pd(II) Catalyzed Enantioselective C(sp³)−H Arylation and Virtual Validation with GABA_B1 Receptor for Potential leads

Article

Author: Mohanlal, Smitha ; Acharya, Rudresh ; Pandey, Shubhant ; Saha, Diprupa ; Sharma, Nagendra K.

AbstractGABA (γ–amino butyric acid) analogues like baclofen, tolibut, phenibut, etc., are well–known GABAB1 inhibitors and pharmaceutically important drugs. However, there is a huge demand for more chiral GABA aryl analogues with promising pharmacological actions. Here, we demonstrate the chiral ligand acetyl–protected amino quinoline (APAQ) mediated enantioselective synthesis of GABAB1 inhibitor drug scaffolds from easily accessible GABA via Pd–catalyzed C(sp3)−H activation. The synthetic methodology shows moderate to good yields, up to 74% of ee. We have successfully demonstrated the deprotection and removal of the directing group to synthesize R–tolibut in 86% yield. Further, we employed computation to probe the binding of R–GABA analogues to the extracellular domain of the human GABAB1 receptor. Our Rosetta–based molecular docking calculations show better binding for four R–enantiomers of GABA analogues than R–baclofen and R–phenibut. In addition, we employed GROMACS MD simulations and MMPB(GB)SA calculations to identify per–residue contribution to binding free energy. Our computational results suggest analogues (3R)‐4‐amino‐3‐(3,4‐dimethylphenyl) butanoic acid, (3R)‐4‐amino‐3‐(3‐fluorophenyl) butanoic acid, (3R)‐3‐(4‐acetylphenyl)‐4‐aminobutanoic acid, (3R)‐4‐amino‐3‐(4‐methoxyphenyl) butanoic acid, and (3R)‐4‐amino‐3‐phenylbutanoic acid are potential leads which could be synthesized from our methodology reported here.

News (Medical) associated with Arbaclofen Placarbil

14 Jul 2022

·www.prnewswire.com

Allos Pharma Inc. presents new positive data analyses at the 18th NFXF International Fragile X Conference

CAMBRIDGE, Mass., July 14, 2022 /PRNewswire/ -- Allos Pharma Inc ("Allos"), a late-stage pharmaceutical company developing therapeutics for neurodevelopmental disorders, announces presentation of "Arbaclofen produces clinically meaningful improvements in individuals with Fragile X" at the 18th NFXF International Fragile X Conference, July 14-17th, 2022. Allos Pharma was founded to translate breakthrough discoveries in neurobiology into innovative drug treatments that improve the lives of patients and families with Fragile X Syndrome, autism, and other disorders of brain development. Meaningful change thresholds (MCTs) were applied for improvement on three subscales of the Fragile X-specific aberrant behavior checklist (ABCFX), Irritability, Social Avoidance and Socially Unresponsive/Lethargic to assess efficacy in the Phase 3 trial in children, aged 5-11. Clinically meaningful magnitudes of improvement were observed on all three ABCFX subscales for 45% of individuals receiving the high dose of arbaclofen vs 4% of those treated with placebo (P=0.00003), clearly demonstrating the efficacy of arbaclofen in individuals with Fragile X. "These findings comport remarkably well with experiences reported by clinicians involved in the clinical trials, who reported that ~50% of those receiving arbaclofen showed clear and substantial improvements." Says Dr. Elizabeth Berry-Kravis, MD, Rush University Medical Center. "We are presenting new analyses of the two phase 3 trials for arbaclofen in Fragile X Syndrome. In addition to the efficacy previously reported, statistically significant efficacy was demonstrated using the current FDA standards for within-subject responder analyses. This represents an important milestone in our work with the regulatory agencies to bring arbaclofen to market" says Randy Carpenter, MD, and co-founder of Allos. "This result supports our hypothesis that arbaclofen correction of core pathophysiology in Fragile X Syndrome arising from dysregulation of neuronal protein synthesis and hyperexcitability will confer broad therapeutic benefit. Combining the new results with the existing literature forms a positive picture of the efficacy of arbaclofen." says Professor Mark Bear and co-founder of Allos. About Allos Pharma, Inc. Headquartered in Cambridge, Massachusetts, Allos Pharma is a late-stage pharmaceutical company developing therapeutics for neurodevelopmental disorders. Our mission is to translate breakthrough discoveries in neurobiology into innovative drug treatments that improve the lives of patients and families with Fragile X Syndrome, autism, and other disorders of brain development. Co-founders Mark Bear and Randy Carpenter previously founded Seaside Therapeutics and advanced arbaclofen through the Phase 3 trials in Fragile X Syndrome. This domain knowledge and expertise will be directly leveraged to advance arbaclofen through NDA approval. For more information visit . Contact: [email protected] SOURCE Allos Pharma Inc.

Innovative Drug

100 Deals associated with Arbaclofen Placarbil

External Link

KEGG	Wiki	ATC	Drug Bank
D08861	Arbaclofen Placarbil	-	DB08892

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Autistic Disorder	Phase 3	US	Allos Pharma, Inc.Startup	14 Jul 2022
Fragile X Syndrome	Phase 3	US	Allos Pharma, Inc.Startup	14 Jul 2022
Alcohol Use Disorder	Discovery	US	Indivior, Inc.	01 Sep 2015
Multiple Sclerosis	Discovery	US	XenoPort, Inc.	01 May 2011
Muscle Spasticity	Discovery	US	XenoPort, Inc.	01 May 2011
Acute low back pain	Discovery	US	XenoPort, Inc.	01 Dec 2008
Spinal Cord Injuries	Discovery	US	XenoPort, Inc.	01 Dec 2007
Gastroesophageal Reflux	Discovery	US	Indivior, Inc.	01 Oct 2005

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