Therapeutics

SUVN-G3031

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Overview

Name: SUVN-G3031
Synonyms: Samelisant, 17v
Chemical Name: N-[4-(1-Cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide Dihydrochloride
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline), Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Suven Life Sciences Ltd

Background

SUVN-G3031 is an orally active histamine H3 receptor antagonist being developed to treat cognitive deficits in Alzheimer's disease and schizophrenia. Histamine H3 receptors are widely expressed in healthy and Alzheimer's disease brains (Medhurst et al., 2009). They exert neuromodulatory functions on the cholinergic, adrenergic, and dopaminergic neurotransmitter systems. Preclinically, inhibiting this receptor has been shown in mice and rats to enhance cholinergic signaling, reduce tau phosphorylation, and reverse behavioral deficits (Medhurst et al., 2007; Bitner et al., 2011). Previous histamine H3 receptor antagonists that were in Phase 2 clinical development for cognition in Alzheimer's include Servier's S 38093, ABT 288, and GSK239512. SUVN-G3031 was described to have nM potency as an inverse against at H3 receptors, and marked wake-promoting activity in rats (Nirogi et al., 2019).

No peer-reviewed scientific studies have been published for SUVN-G3031. At the 2014 AAIC conference, Suven Life Sciences reported positive data on exposure, safety, pharmacokinetics, and behavioral assays in rats. The poster claimed an increase in cortical histamine and acetylcholine levels as well as reversal of memory deficits (Babu et al., 2014). Further preclinical data were presented at AAIC in 2015 (Benade et al., 2015). This work was later published, detailing procognitive effects in tests of social recognition and object recognition. SUVN-G3031 increased brain acetylcholine levels, and acted synergistically with suboptimal doses of donepezil to improve performance in the Morris water maze (Nirogi et al., 2021). At 10 times higher doses, it increased cortical levels of histamine, norepinephrine and dopamine in rats, and promoted wakefulness in rats and mice (Nirogi et al., 2021). The potential for drug-drug interactions was judged to be low, based on in vitro predictive assays (Nirogi et al., 2020).

Findings

Between September 2014 and August 2017, the CRO Quintiles conducted two Phase 1 safety, tolerability, and pharmacokinetics studies in 108 healthy people, mostly men, in the state of Kansas. Results of both trials were published (Nirogi et al., 2020). Single doses up to 20 mg and multiple does up to 6 mg were safe and well-tolerated. The most frequent adverse events were abnormal dreams, trouble falling or staying asleep, and hot flushes. Pharmacokinetics were dose-proportional, and not affected by food, sex, or age. 

No trials are currently registered for cognitive disorders. A Phase 2 study for narcolepsy completed enrolling 190 participants in June 2023, and results are expected in mid-2024.

For registered trials on this compound, see clinicaltrials.gov.

Last Updated: 21 Sep 2023

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References

Therapeutics Citations

  1. S 38093
  2. ABT-288
  3. GSK239512

Paper Citations

  1. Nirogi R, Mudigonda K, Bhyrapuneni G, Muddana NR, Shinde A, Goyal VK, Pandey SK, Mohammed AR, Ravula J, Jetta S, Palacharla VR. 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. Clin Drug Investig. 2020 Jul;40(7):603-615. PubMed.
  2. Medhurst AD, Roberts JC, Lee J, Chen CP, Brown SH, Roman S, Lai MK. Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice. Br J Pharmacol. 2009 May;157(1):130-8. PubMed.
  3. Medhurst AD, Atkins AR, Beresford IJ, Brackenborough K, Briggs MA, Calver AR, Cilia J, Cluderay JE, Crook B, Davis JB, Davis RK, Davis RP, Dawson LA, Foley AG, Gartlon J, Gonzalez MI, Heslop T, Hirst WD, Jennings C, Jones DN, Lacroix LP, Martyn A, Ociepka S, Ray A, Regan CM, Roberts JC, Schogger J, Southam E, Stean TO, Trail BK, Upton N, Wadsworth G, Wald JA, White T, Witherington J, Woolley ML, Worby A, Wilson DM. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther. 2007 Jun;321(3):1032-45. PubMed.
  4. Bitner RS, Markosyan S, Nikkel AL, Brioni JD. In-vivo histamine H3 receptor antagonism activates cellular signaling suggestive of symptomatic and disease modifying efficacy in Alzheimer's disease. Neuropharmacology. 2011 Feb-Mar;60(2-3):460-6. Epub 2010 Oct 31 PubMed.
  5. Nirogi R, Shinde A, Mohammed AR, Badange RK, Reballi V, Bandyala TR, Saraf SK, Bojja K, Manchineella S, Achanta PK, Kandukuri KK, Subramanian R, Benade V, Palacharla RC, Jayarajan P, Pandey S, Jasti V. Discovery and Development of N-[4-(1-Cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide Dihydrochloride (SUVN-G3031): A Novel, Potent, Selective, and Orally Active Histamine H3 Receptor Inverse Agonist with Robust Wake-Promoting Activity. J Med Chem. 2019 Feb 14;62(3):1203-1217. Epub 2019 Jan 25 PubMed.
  6. Babu MR, Nageswararao Muddana N, Mekala VR, P Jayarajan, Kanamarlapudi VB, Faheem MA, A, Irappanavar S, Goyal VK, Pandey SK, Gangadasari PN, Ponnamaneni R, Nirogi R. SUVN-G3031: A Novel and Potent Histamine H3 Receptor Antagonist for Potential Treatment of Cognitive Deficits. July 2014, Volume 10, Issue 4, Supplement, Pages P459–P460
  7. Benade VS, Saivishal Daripelli S, Thentu JB, Manoharan A, Medapati RB, Subramanian R, Mekala VR, Shinde AK, Badange RK, Goyal VK, Pandey SK, Nirogi R. Suvn-g3031, an h3 receptor inverse agonist, produces procognitive effects without affecting sleep in preclinical models. July 2015, Volume 11, Issue 7, Supplement, Page 475
  8. Nirogi R, Grandhi VR, Medapati RB, Ganuga N, Benade V, Gandipudi S, Manoharan A, Abraham R, Jayarajan P, Bhyrapuneni G, Shinde A, Badange RK, Subramanian R, Petlu S, Jasti V. Histamine 3 receptor inverse agonist Samelisant (SUVN-G3031): Pharmacological characterization of an investigational agent for the treatment of cognitive disorders. J Psychopharmacol. 2021 Jun;35(6):713-729. Epub 2021 Feb 5 PubMed.
  9. Nirogi R, Benade V, Daripelli S, Subramanian R, Kamuju V, Bhyrapuneni G, Muddana NR, Mekala VR, Petlu S, Jayarajan P, Badange R, Shinde A, Jasti V. Samelisant (SUVN-G3031), a potent, selective and orally active histamine H3 receptor inverse agonist for the potential treatment of narcolepsy: pharmacological and neurochemical characterisation. Psychopharmacology (Berl). 2021 Jun;238(6):1495-1511. Epub 2021 Feb 7 PubMed.
  10. Nirogi R, Bhyrapuneni G, Muddana NR, Manoharan A, Shinde AK, Mohammed AR, Padala NP, Ajjala DR, Subramanian R, Palacharla VR. Absorption, distribution, metabolism, excretion (ADME), drug-drug interaction potential and prediction of human pharmacokinetics of SUVN-G3031, a novel histamine 3 receptor (H3R) inverse agonist in clinical development for the treatment of narcolepsy. Eur J Pharm Sci. 2020 Sep 1;152:105425. Epub 2020 Jun 10 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Nirogi R, Ajjala DR, Prakash Padala NS, Kalaikadhiban I, Rayapati LP, Chunduru P, Shinde A. LC-MS/MS method for the quantification of SUVN-G3031, a novel H3 receptor inverse agonist for narcolepsy treatment. Bioanalysis. 2020 Apr;12(8):533-544. Epub 2020 Apr 30 PubMed.