Ramkumar Subramanian

Synthesis and SAR of Imidazo[1,5-a]pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease.

Alzheimers disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition.

Design, Synthesis and Pharmacological Evaluation of Piperidin-4- yl amino aryl sulfonamides: Novel, Potent, Selective, Orally Active and Brain Penetrant 5-HT6 Receptor Antagonists

Our initial findings around aryl sulfonamide series led to N-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy benzenesulfonamide as potent and selective 5-HT(6) receptor (5-HT(6)R) antagonist with reasonable pharmacokinetic properties and activity in animal models of cognition. However, lack of brain penetration and P-glycoprotein liability makes this scaffold unsuitable for further development. Our goal was to identify small molecule 5-HT(6)R antagonist with adequate brain penetration, acceptable ADME properties, no P-glycoprotein, and no hERG liability. Several structural modifications including bringing conformational constraint around the sulfonamide -NH group and introduction of a heteroatom to modulate the physicochemical properties were attempted. This effort culminated in the discovery of series of novel, potent, selective, orally bioavailable, and adequately brain penetrant compounds with no hERG liability. These compounds showed activity in animal models of cognition like object recognition task and water maze and in brain microdialysis studies at lower doses.

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of 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 channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of 5al, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT2A receptors are the differentiating features which culminated in selection of 5al for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study.

SUVN-G3031, A POTENT AND SELECTIVE H3 RECEPTOR INVERSE AGONIST: SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HUMANS

Background:Several types of MT have approved benefits in AD via rehabilitation and psychiatric care. However, there are few studies of MT on neurophysiological function using event-related potentials (ERP). Methods:We consecutively recruited mild AD cases (Clinical dementia rating1⁄4 0.5w1), who voluntarily separated into MT group or control group (CG) for 3 months course. These assessments of clinical MTeffect were including Mini-mental state examination (MMSE), Cognitive abilities screening instrument (CASI) in both groups, and ERP only in MT group. The intervention mode of MT was using the medical resonance therapy music (RRR 128 for concentration/memory and RRR 931 for relaxation), separately listening by headphone for 30 minutes in the daily morning and before sleep respectively. Results:There were 23 and 20 cases in MT and CG group respectively. The baseline ERP N200 (N2) and P300 (P3) responses of MT were poor (eg. Mean CzN21⁄4290.1637.81 ms and CzP31⁄4445.2671.29 ms). After comparing the two groups data, we found the differences of MMSE & CASI after 3 months in MT (0.463.49 & -2.567.53) were better than CG (-2.465.51 & -5.8618.12). But they were not statistically significant (p1⁄40.051 & 0.458). Further adjusting by gender, age, education level and corresponding baselinemeasures in analysis of covariance, we found adjusted differences of MMSE and CASI in MTwere slightly better than those in CG, yet without statistical significance. In the assessments of ERP in MT, the 3 months differences of P3 amplitude in Fz and Cz sites were significantly increasing (5.266.87 mV and 2.463.31 mV, p1⁄40.030 and 0.024). The 3 months differences of all N2 components, P3 latency, accurate response rate and mean responsive time were improving, yet not reaching statistical significance. Conclusions: The AD patients had poor cognitive process, even in very early and mild stage. The three-monthmedical resonance therapymusic shows significant effect on responsive intensity of information processing in mild AD patients. No apparently additional benefits of this MTwere noted in the globally cognitive assessments for 3 months.

Suvn-g3031, an h3 receptor inverse agonist, produces procognitive effects without affecting sleep in preclinical models

Background: Serotonin receptor, subtype 4 (5-HT4) is involved in memory formation. It modulates the cholinergic pathway through the release of acetylcholine from the cholinergic neurons. Activation of 5-HT4 receptor directs processing of amyloid precursor protein (APP) towards non-amyloidogenic form and also promotes the formation of the neurotrophic sAPPa. Therefore 5-HT4 agonist may offer a unique treatment for Alzheimer’s disease (AD). Methods: The procognitive property of SUVN-D4010, a potent, selective and orally bioavailable 5-HT4 partial agonist was characterized in animals models of cognition like object recognition task, radial arm maze task and fear conditioning assay. The effect on the cholinergic neurotransmission was studied using brain microdialysis technique. In vivo receptor binding profile was measured using non-radiolabeled tracer in rats. The effect of SUVN-D4010 on the toxic b-amyloid and the neuroprotective sAPPa were evaluated in the preclinical species using ELISA kits. Safety, general toxicity and mutagenic potential of SUVND4010 were evaluated in rodents/non rodents and in vitro models. Results: SUVN-D4010 improved the episodic memory deficits in object recognition task. It also reversed the working and emotional memory deficits induced by scopolamine in radial arm maze task and fear conditioning assay. Oral administration of SUVN-D4010 significantly increased the brain acetylcholine levels. The effect on the cognition and cholinergic neurotransmission were blocked byGR 125478, a selective 5-HT4 antagonist. SUVN-D4010 showed significant 5-HT4 receptor occupancy at pharmacologically effective doses. A significant increase in cortical sAPPa and decrease in amyloid-b protein levels was also seen. SUVN-D4010 was well tolerated in animal toxicity studies and did not show any mutagenic potential. Conclusions: SUVN-D4010 is a novel, potent, selective, orally bioavailable, efficacious and a safe 5-HT4 receptor partial agonist. IND enabling GLP safety studies have been completed. US IND filing and Phase I studies are currently being planned.

Suvn-d4010: A novel 5-ht4 receptor partial agonist for the treatment of Alzheimer’s disease

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder of advanced age characterized by loss of memory, accumulation of amyloid beta protein (Ab) deposits and decreased levels of the neurotransmitter acetylcholine. 5-HT4 receptor partial agonists may be of benefit for both the symptomatic and disease-modifying treatment for AD and may offer improved clinical efficacy and/or tolerability relative to acetylcholine esterase inhibitors. Methods: SUVN-D4010 a potent, selective and orally bioavailable 5-HT4 partial agonist was evaluated for its procognitive properties in object recognition task, radial arm maze task and fear conditioning assay. Modulation of acetylcholine levels by SUVN-D4010 was evaluated using brain microdialysis technique. Striatal 5-HT4 receptor occupancy was measured using non-radiolabeled tracer in rats. Cortical sAPPa levels and CSF amyloid-b protein levels were also evaluated in the preclinical species using ELISA kits. Safety, general toxicity and mutagenic potential of SUVN-D4010 were evaluated in rodents/non rodents and in-vitro models. Results: SUVN-D4010 reversed the episodic memory deficits in object recognition task, working and emotional memory deficits induced by scopolamine in radial arm maze task and fear conditioning assay. Oral administration of SUVN-D4010 significantly increased the brain acetylcholine levels. The effect observed was blocked by a selective 5-HT4 antagonist. SUVN-D4010 showed a dose dependent increase in receptor occupancy in rat brain. A significant increase in cortical sAPPa and decrease in CSF amyloid-b protein levels was noted in non-transgenic animal models. SUVN-D4010 was well tolerated in animal toxicity studies and did not show any mutagenic potential in-vitro.Conclusions: SUVN-D4010 is a novel, potent, selective, orally bio-available, efficacious and safe 5-HT4 receptor partial agonist. IND enabling studies are completed and US IND filing is in progress.

SUVN-G3031, A SELECTIVE H3 RECEPTOR INVERSE AGONIST: ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

treatment detected blood Ab1-42and p tau 181 levels, and comparison with normal old subjects. Results:Data from 20 AD patients were analyzed in this study. The ADAS-cog score in the treatment group was significantly improved compared to the sham group (ADAS-cog(P1⁄40.003), MMSE (p1⁄40.014), ACE—III (p1⁄40.004)), ADL (P1⁄40.014. Resting-state functional MRI shows brain functional connections related to cognition changing, including the connection between left prefrontal cortex and left inferior frontal gyrus, the right prefrontal cortex and the right cerebellum; but there is no link to other regions in the left temporal lobe. Blood tests found that in experimental group Ab1-42 was lower than those of normal aging control (P 1⁄4 0.04), before and after treatment Ab1-42(P 1⁄4 0.15), group treatment has a rising trend; P tau 181 content was higher than normal aging (p 1⁄4 0.06), treatment has a declining trend, but without statistical significance. Conclusions:The present results suggest that high-frequency rTMS represents a useful adjuvant therapy with AD, which can improve cognitive function and its possible mechanism of magnetic stimulation improving brain function in the left prefrontal cortex is associated with other cognitive function connection area. In addition, rTMS may also affect the patients with pathological markers Ab1-42 / p tau 181, which may also be one of its therapeutic mechanism.

Synthesis, Structure–Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists

Alzheimers disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.

SUVN-M8036, A SEROTONERGIC AND DOPAMINERGIC MODULATOR, ALLEVIATES PSYCHOSIS AND DEPRESSION

predicting ReHo from cumulative SBP and DBP adjusted for age, sex and race. Results: Greater SBP was associated with lesser ReHo in the bilateral hippocampi, left insula, right lingual, precentral and middle temporal gyri. Greater DBP was associated with lesser ReHo in the bilateral hippocampi, lingual and superior temporal gyri and brainstem and the left temporal pole, right frontal pole and inferior frontal gyrus. Greater DBP was also associated with greater ReHo in the left frontal pole. Conclusions:Greater cumulative BP exposure during young adulthood through midlife is associated with lesser local connectivity in various brain regions linked to cognitive performance, in particular, bilateral hippocampi. The link between BP and hippocampal connectivity is particularly intriguing in the context of established impact of cardiovascular risk factors on Alzheimer’s disease.

NEUROCHEMICAL AND ELECTROPHYSIOLOGICAL CHARACTERIZATION OF SUVN-I6107, A NOVEL MUSCARINIC M1 RECEPTOR POSITIVE ALLOSTERIC MODULATOR

amplitude all showed a decrease in the placebo group, whereas they increased in the PQ912 group, indicating an improved global functional connectivity in the latter. The AEC showed a significant effect (mean change: placebo1⁄4-0.0054 versus PQ9121⁄40.0044, t-test: p1⁄40.025, Cohen’s d1⁄40.45) and the TCR-amp showed a trend (mean change: placebo1⁄4-0.0012 versus PQ9121⁄40.0018, p1⁄40.065, d1⁄40.37). The effect measured by AEC remained significant when corrected for sex, country, ApoE, age and baseline value, and additionally for EEG measures of oscillatory activity (global relative power measures in 5 frequency bands; both ANCOVA models p<0.05). There was no correlation between global relative theta power and AEC (r1⁄40.12, p1⁄40.22). Conclusions: Functional connectivity, measured with AEC, significantly improved with PQ912 treatment compared to placebo. This effect sustained when corrected for demographic variables, baseline value and EEG relative power measures.