A5081216144- Cholinesterase and Neurodegenerative Diseases
- Receptor Mechanisms and Signaling
- Pharmacogenetics and Drug Metabolism
- Sleep and Wakefulness Research
- Chemical synthesis and alkaloids
- Computational Drug Discovery Methods
- Neuroscience and Neuropharmacology Research
- Circadian rhythm and melatonin
- Drug Transport and Resistance Mechanisms
- Treatment of Major Depression
- Nicotinic Acetylcholine Receptors Study
- Photochromic and Fluorescence Chemistry
- Neurological Disorders and Treatments
- Analytical Chemistry and Chromatography
- Phosphodiesterase function and regulation
- Mast cells and histamine
- Olfactory and Sensory Function Studies
- Pharmacological Effects and Toxicity Studies
- Neurotransmitter Receptor Influence on Behavior
- Neuropeptides and Animal Physiology
- Drug-Induced Hepatotoxicity and Protection
- Synthesis and Biological Evaluation
- Analytical Methods in Pharmaceuticals
- Dementia and Cognitive Impairment Research
- Cancer therapeutics and mechanisms
Suven Life Sciences (India)
2016-2025
In Vitro Admet Laboratories (United States)
2019
Optimization of a novel series 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) clinical candidate for potential treatment cognitive disorders. It has high affinity at human 5-HT6R (Ki = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion...
1. Chemical inhibition is the widely used method in reaction phenotyping assays for estimation of specific enzyme contribution to a given metabolic pathway. The results from depend on selectivity chemical inhibitor and concentration incubation.2. higher protein concentrations vitro will impact inhibitory potency inhibitors. objective study evaluate comprehensively inhibitors guide selecting appropriate be based unbound fractions.3. Selectivity against nine major CYP450 isoforms was...
Abstract Introduction Samelisant (SUVN-G3031) is potent and selective histamine 3 receptor inverse agonist, which works by modulating the system, a key part of brain’s sleep-wake regulation. demonstrated wake-promoting anticataplectic effects, in animal models relevant to narcolepsy. Methods was evaluated orexin knockout mice orexin-B SAP lesioned rats for its effects on sleep/ wake cataplexy using electroencephalography (EEG). produced significant reduction cataplectic like episodes mice,...
1. Aldehyde oxidase (AO) is a liver cytosolic molybdoflavoprotein enzyme whose importance in drug metabolism gaining the recent. The objective of this work to find potent and selective inhibitor for AO activity using phthalazine oxidation as marker reaction. 2. Among organic solvents tested, it was identified that methanol not suitable choice even at concentrations less than 0.2% v/v. Acetonitrile DMSO did show any effect till 0.5% v/v but thereafter activites tend decrease. 3. For...
Alzheimer's disease (AD) is a neurodegenerative disorder that has higher prevalence and incidence in people older than 60 years. The need for improved AD therapies unmet as the current are symptomatic with modest efficacy. Partial agonists of 5-HT4 receptor (5-HT4R) offer both disease-modifying treatments they shift amyloid-precursor-protein (APP) processing from amyloidogenic pathway to nonamyloidogenic by activating α-secretase enzyme. In addition, also treatment increasing levels...
A series of chemical optimizations guided by in vitro affinity at the α4β2 receptor combination with selectivity against α3β4 receptor, pharmacokinetic evaluation, and vivo efficacy a forced swim test resulted identification 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as clinical candidate. Compound 9h is potent ligand Ki value 1.5 nM. It showed >10 μM binding toward ganglionic apart from showing over 70 other targets. orally bioavailable good...
A series of chemical optimizations guided by in vitro affinity at a histamine H3 receptor (H3R), physicochemical properties, and pharmacokinetics rats resulted identification N-[4-(1-cyclobutyl-piperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide dihydrochloride (17v, SUVN-G3031) as clinical candidate. Compound 17v is potent (hH3R Ki = 8.73 nM) inverse agonist H3R with selectivity over other 70 targets, has adequate oral exposures favorable elimination half-lives both dogs. It demonstrated...
A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, systematic structure–activity relationship was conducted, which led to discovery potent selective agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced...
1. Determination of fm, CYP for a compound is critical to assess the potential risk drug candidate as victim DDI. Several compounds are identified CYP2B6 substrates, but values not determined quantitatively. 2. Two methods reaction phenotyping, chemical inhibition method and metabolism in rCYP enzymes, were used determine relative contributions enzymes. Chemical was also conducted presence BSA (0.5% w/v). 3. The results confirm with earlier studies concerning identity enzyme. artemisinin,...
In this study, we report the effect of dimethyl sulfoxide (DMSO), acetonitrile, and methanol on CYP1A2-mediated metabolism phenacetin in human liver microsomes. Phenacetin O-deethylation is preferred probe reaction for CYP1A2, which metabolite, acetaminophen, quantified using liquid chromatography-tandem mass spectrometry. DMSO was found to inhibit even at low concentrations (0.1%). Acetonitrile did not significantly change activity up 2%. There no when present levels We that level should be...
The objective is to evaluate methoxsalen as an in vitro phenotyping tool comparison ABT a nonspecific inactivator of P450 mediated metabolism. reversible inhibition and against the P450, FMO, AO, MAO-A -B, enzymes were evaluated using standard marker probe reactions. time-dependent was human liver microsomes. CES1 activities determined by monitoring depletion known substrate, clopidogrel. metabolism substrates presence absence or Methoxsalen direct inhibitor inhibited (>90%) all at...
Unbound drug concentration in the brain would be true exposure responsible for specific target occupancy. Drug exposures from preclinical are total concentrations of those over/underestimate clinical dose projection. With application mass spectrometry, current work proposes a definite measure test at serotonin-2A The 5-HT2A occupancy antagonist rat has determined with non-radiolabeled tracer MDL-100,907 an optimized (3 µg/kg) and treatment time (30 min). Equilibrium dialysis method...