Determination of Intrinsic Clearance and Fraction Unbound in Human Liver Microsomes and In Vitro-In Vivo Extrapolation of Human Hepatic Clearance for Marketed Central Nervous System Drugs.

Objective: The objective of this study was to determine the apparent intrinsic clearance (Cl) and fraction unbound in human liver microsomes (f) of 86 marketed central nervous system (CNS) drugs and to predict the in vivo hepatic blood clearance (CL).

Methods: Cl in human liver microsomes (HLM) was determined by substrate depletion, and f was determined by equilibrium dialysis. The relationship between lipophilicity (logP) and unbound intrinsic clearance (Cl) was explored using the Biopharmaceutical Drug Disposition Classification System (BDDCS) and Extended Clearance Classification System (ECCS).

Samelisant (SUVN-G3031), a histamine 3 receptor inverse agonist: Results from the phase 2 double-blind randomized placebo-controlled study for the treatment of excessive daytime sleepiness in adult patients with narcolepsy.

Narcolepsy is a rare, chronic neurological disorder characterized by a dysregulated sleep-wake cycle, with core clinical features including excessive daytime sleepiness (EDS), cataplexy, hypnopompic/hypnagogic hallucinations, and sleep paralysis. Several treatment options are available for the symptomatic management of narcolepsy, but they have limitations. Comorbidities of narcolepsy further limit the treatment choices.

Hits and misses with animal models of narcolepsy and the implications for drug discovery.

Introduction: Narcolepsy is a chronic and rare neurological disorder characterized by disordered sleep. Based on animal models and further research in humans, the dysfunctional orexin system was identified as a contributing factor to the pathophysiology of narcolepsy. Animal models played a larger role in the discovery of some of the pharmacological agents with established benefit/risk profiles.

Bioequivalence, food effect and comparative pharmacokinetics of SUVN-1105, a novel granule formulation of abiraterone acetate, to Zytiga in healthy male subjects.

Purpose: SUVN-1105 is a novel formulation of abiraterone acetate which was developed to demonstrate improved bioavailability, compared to Zytiga and Yonsa, and to reduce the dose and eliminate the food effect. A Phase 1 study was conducted to assess the bioequivalence, food effect, and comparative pharmacokinetics of SUVN-1105 to Zytiga in healthy male subjects.

Methods: The study comprised of 2 segments.

Review on 505(b)(2) Drug Products Approved by USFDA from 2010 to 2020 Emphasizing Intellectual Property and Regulatory Considerations for Reformulations and New Combinations.

Repurposing is considered an attractive approach for developing new drug products. However, it consists of challenges relating to intellectual property (IP) protection, and regulatory approvals. This study aimed to analyze the recent trends in repurposed drugs approved by USFDA from 2010 to 2020 and to assess the challenges connected with bridging study requirements, patent protection, and exclusivities.

Usmarapride (SUVN-D4010), a 5-HT receptor partial agonist for the potential treatment of Alzheimer's disease: Behavioural, neurochemical and pharmacological profiling.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which affects cognitive functions with negative impact on day to day activities and an ultimate loss of independent living. Current standard of care (SOC) for AD, viz. donepezil, rivastigmine, galantamine, memantine etc.

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders.

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT) receptor has been an area of substantial research. 5-HT receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways.

Safety, Tolerability, and Pharmacokinetics of Ropanicant (SUVN-911), a Novel Alpha4 Beta2 Nicotinic Acetylcholine Receptor (α4β2 nAChR) Antagonist, in Healthy Adult and Elderly Subjects.

Background And Objectives: Ropanicant hydrochloride (previously known as SUVN-911, hereinafter referred to as ropanicant) is a novel alpha4 beta2 nicotinic acetylcholine receptor (α4β2 nAchR) antagonist being developed for the treatment of major depressive disorder. The objectives of the present studies were to evaluate the safety, tolerability, and pharmacokinetics of ropanicant after single and multiple ascending doses and to evaluate the effect of food, sex, and age on its pharmacokinetics in healthy subjects.

Methods: Two phase I studies have been conducted for ropanicant.

Effect of Concurrent Use of Memantine on the Efficacy of Masupirdine (SUVN-502): A Post Hoc Analysis of a Phase 2 Randomized Placebo-Controlled Study.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, memory and activities of daily living. Selective blockade of serotonin-6 (5-HT) receptors, which are exclusively localized to the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5-HT receptor antagonist with pro-cognitive properties in animal models of cognition.

Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer's disease: A randomized, double-blind, phase 2, proof-of-concept study.

Introduction: This study explored the efficacy and safety of a serotonin-6 receptor antagonist, masupirdine, as adjunct treatment in patients with moderate Alzheimer's disease (AD) concomitantly treated with donepezil and memantine.

Methods: The effects of masupirdine were evaluated in patients with moderate AD dementia on background treatment with donepezil and memantine. Five hundred thirty-seven patients were expected to be randomized in a 1:1:1 ratio, using permuted blocked randomization.

Ropanicant (SUVN-911), an α4β2 nicotinic acetylcholine receptor antagonist intended for the treatment of depressive disorders: pharmacological, behavioral, and neurochemical characterization.

Rationale: Ropanicant (SUVN-911) (3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo (3.1.0) hexane hydrochloride) is a novel α4β2 nicotinic acetylcholine receptor (nAChR) antagonist being developed for the treatment of depressive disorders.

A selective and accurate liquid chromatography-tandem mass spectrometry method for the quantitation of the novel 5-HT receptor partial agonist SUVN-D4010 (Usmarapride) in human plasma and urine.

Liquid chromatography and the tandem mass spectrometry method to quantitate SUVN-D4010 (Usmarapride) in human plasma and urine have been developed and fully validated in compliance with regulatory guidelines. The sample preparation technique is simple and rapid consisting of acetonitrile precipitation followed by dilution of supernatant with a compatible solvent. Chromatographic separation was achieved on an X-Bridge C (2.

1-[2-(1-Cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one: a Histamine H Receptor Inverse Agonist with Efficacy in Animal Models of Cognition.

A series of chemical optimizations, which was guided by in vitro affinity at histamine H receptor (H R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one (45 e) as a potent and selective (K =4.0 nM) H R inverse agonist. Dipsogenia induced by (R)-α-methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H R.

Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease.

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HTR) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HTR antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HTR partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, ). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models.

First-in-Human Studies to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Novel 5-HT Partial Agonist, SUVN-D4010, in Healthy Adult and Elderly Subjects.

Background And Objective: SUVN-D4010 is a novel, potent, highly selective 5-HT partial agonist intended for the treatment of cognitive disorders. The objective of the clinical study was to characterize the safety, tolerability, and pharmacokinetics of SUVN-D4010 in healthy adults after single and multiple doses, and to evaluate the effect of food, sex, and age on the pharmacokinetics.

Methods: Single-ascending dose and multiple-ascending dose studies for 14 days were conducted in healthy adults using a randomized, double-blind design.

Evaluation of monoamine oxidase A and B type enzyme occupancy using non-radiolabelled tracers in rat brain.

Monoamine oxidase (MAO) enzymes, type A and B metabolise the amine neurotransmitters of the body. Selective inhibition of either enzyme is an approach for treating neurodegenerative and stress-induced disorders, and inhibition of an enzyme is proportional to the binding of the MAO inhibitor. Conventionally, the binding of test compounds to enzymes is assessed by radiolabelled ligands in ex vivo and in vivo occupancy assays.

Samelisant (SUVN-G3031), a potent, selective and orally active histamine H3 receptor inverse agonist for the potential treatment of narcolepsy: pharmacological and neurochemical characterisation.

Rationale: Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability.

Objectives: Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy.

Methods: Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine.

Histamine 3 receptor inverse agonist Samelisant (SUVN-G3031): Pharmacological characterization of an investigational agent for the treatment of cognitive disorders.

Background: Central histamine H3 receptors are a family of presynaptic auto and heteroreceptors. Blockade of the presynaptic H3 receptors activates the downstream pathway(s) involved in the processes of learning and memory, making it a potential therapeutic option for ameliorating cognitive dysfunction. Samelisant (SUVN-G3031) is a potent and selective inverse agonist at the H3 receptors.

Short-term toxicity study of 1-aminobenzotraizole, a CYP inhibitor, in Wistar rats.

1-Aminobenzotriazole (ABT) is a pan-specific, mechanism-based inhibitor of CYP P450 enzymes, often used as co-treatment to investigate the metabolism-dependent toxicity of drugs or chemicals. To assess the confounding effects of ABT in such kind of mechanistic studies, a repeated dose toxicity study with ABT following 7 days oral administration at 0, 25, 50 and 100 mg/kg/day was performed in Wistar rats (5 rats/sex/group). Wistar rat is selected as a model being one of the well characterized rodent species, widely used for toxicity and toxicokinetics studies.

Absorption, distribution, metabolism, excretion (ADME), drug-drug interaction potential and prediction of human pharmacokinetics of SUVN-G3031, a novel histamine 3 receptor (HR) inverse agonist in clinical development for the treatment of narcolepsy.

SUVN-G3031 is a potent and selective inverse agonist of Histmine-3 (H) receptor that is being investigated for the treatment of narcolepsy. SUVN-G3031 has high passive permeability, not a substrate for P-glycoprotein, has high plasma unbound fractions and was equally distributed between blood and plasma. Major routes of metabolism in vitro were cyclization (Metabolite A) in microsomes and dealkylation (Metabolite D) in hepatocytes.

The use of inactivated brain homogenate to determine the fraction unbound in brain for unstable compounds.

The use of IBH-5 decreased the values and increased the half-life of the compounds PNZ, TCP, Cpd I and Cpd II with values of 1.10 × 10s ( 115 min), 4 × 10s ( = 289 min), 4 × 10s ( = 289 min), and 3 × 10 s ( = 385 min) respectively, compared to values of 1.25 × 10 s ( = 0.

Safety, Tolerability, and Pharmacokinetics of SUVN-G3031, a Novel Histamine-3 Receptor Inverse Agonist for the Treatment of Narcolepsy, in Healthy Human Subjects Following Single and Multiple Oral Doses.

Background And Objective: SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (HR) inverse agonist in development for the treatment of narcolepsy. Our objective was to characterize the safety, tolerability, and pharmacokinetics of SUVN-G3031 in healthy young adults after single and multiple doses, and to evaluate the effect of food, gender, and age on the pharmacokinetics.

Methods: A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design.

LC-MS/MS method for the quantification of SUVN-G3031, a novel H3 receptor inverse agonist for narcolepsy treatment.

A LC-MS/MS method was validated for the quantification of SUVN-G3031, a novel H3 receptor inverse agonist in clinical development for the treatment of patients with narcolepsy, with and without cataplexy. SUVN-G3031 was extracted from plasma following acetonitrile protein precipitation, separated by Ultra HPLC and quantified using positive ESI-MS/MS. The method was linear across the range of 0.

Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression.

A series of chemical optimizations guided by in vitro affinity at the α4β2 receptor in combination with selectivity against the α3β4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (, SUVN-911) as a clinical candidate.