P1‐397: Suvn‐g3031: a Novel and Potent Histamine H3 Receptor Antagonist for Potential Treatment of Cognitive Deficits
Year: 2014
Type: article
Abstract: H 3 receptors play a critical role as neuromodulators through their widespread distribution in the central nervous system. Blockade of this receptor augments the pre-synaptic release of both histamine and other neurotransmitters including acetylcholine from cholinergic neurons. Currently, several H 3 receptor antagonists/inverse agonists are in different stages of clinical trials for the potential treatment of narcolepsy, cognitive impairments associated with Alzheimer's disease, Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. In vitro affinity and selectivity profile was assessed in suitable systems. Pharmacokinetic and brain penetration was evaluated in male Wistar rats. In-vivo receptor occupancy was carried at various dose levels using non-radiolabled tracer. SUVN-G3031 was evaluated in H 3 agonist induced dipsogenia assay and rat models of cognition like object recognition task, T-maze and Morris water maze task. Effect of SUVN-G3031 on histamine and acetylcholine modulation in brain was studied using microdialysis. Toxicity profile of SUVN-G3031 was evaluated in rodents/ non rodents and In vitro models. SUVN-G3031 is one of the lead molecules with hKi of 8.7 nM and has more than 100 fold selectivity against the related GPCRs. SUVN-G3031 exhibited desired pharmacokinetic property and brain penetration. This molecule exhibited an excellent separation between H 3 affinity and hERG ion channel inhibition. SUVN-G3031 blocked R-α-methylhistamine induced water intake and increased tele -methylhistamine levels in brain and cerebrospinal fluid. Treatment with SUVN-G3031 significantly reversed time induced memory deficit in novel object recognition test & T-maze task and scopolamine induced memory deficit in Morris water maze task. A single oral administration resulted in H 3 receptor occupancy up to 85% in rats and significantly raised acetylcholine and histamine levels in the cortex. SUVN-G3031 was well tolerated in toxicity studies in animals with wide margin of safety and is non mutagenic. SUVN-G3031 displayed desired efficacy, safety, pharmacokinetic and metabolic profiles for further development. IND enabling studies are completed and US IND filing is in progress.
Source: Alzheimer s & Dementia
Authors: Medapati Rajesh Babu, Nageswararao Muddana, Venkat Reddy Mekala, Pradeep Jayarajan, Vijaya Bhargava Kanamarlapudi, Mohammed Abdul Faheem, Anil Shinde, Shantaveer Irappanavar, Vinod Kumar Goyal, Santosh Kumar Pandey, Pamuleti Narasimhareddy Gangadasari, Ranjithkumar Ponnamaneni, Ramakrishna Nirogi
Institution: Suven Life Sciences (India)
Language: English
Topic: Mast cells and histamine
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2008404870