Enerisant

Enerisant
Clinical data
Other names	TS-091
Routes of; administration	By mouth
Pharmacokinetic data
Protein binding	31.0–31.7%
Elimination half-life	8 hours
Excretion	Kidney (64.5–89.9%)
Identifiers
	IUPAC name [1-[4-[3-[(2R)-2-methylpyrrolidin-1-yl]propoxy]phenyl]pyrazol-4-yl]-morpholin-4-ylmethanone;
CAS Number	1152747-82-4;
PubChem CID	42601503;
ChemSpider	44208825;
UNII	E2Y97PQY3A;
Chemical and physical data
Formula	C22H30N4O3
Molar mass	398.507 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H]1CCCN1CCCOC2=CC=C(C=C2)N3C=C(C=N3)C(=O)N4CCOCC4;
	InChI InChI=1S/C22H30N4O3/c1-18-4-2-9-24(18)10-3-13-29-21-7-5-20(6-8-21)26-17-19(16-23-26)22(27)25-11-14-28-15-12-25/h5-8,16-18H,2-4,9-15H2,1H3/t18-/m1/s1; Key:IABXVJILZYNSTM-GOSISDBHSA-N;

Enerisant is an experimental histamine H₃ receptor antagonist/inverse agonist being investigated as a potential treatment for sleep-wake disorders, particularly narcolepsy.^[1]^[2]^[3]

Pharmacology

Pharmacodynamics

Enerisant functions as a potent and highly selective antagonist/inverse agonist of the histamine H₃ receptor. This mechanism of action is similar to that of pitolisant, a currently approved H₃ receptor antagonist/inverse agonist for narcolepsy; however, enerisant has demonstrated greater affinity and selectivity for the H₃ receptor in preclinical studies.^[1]^[2]^[3]^[4]^[5] By blocking H₃ receptors, enerisant increases histamine release from histaminergic neurons, leading to stimulation of postsynaptic histamine H₁ receptors, a key mechanism in promoting wakefulness^[1]^[3]^[4]

Pharmacokinetics

Enerisant exhibits minimal metabolism in humans and is primarily eliminated unchanged via renal excretion. After oral administration, it rapidly absorbs and exhibits dose-dependent plasma concentrations. Within 48 hours, 64.5-89.9% of the administered dose is recovered unchanged in urine. Plasma protein binding is approximately 31.0–31.7% in humans.^[1]^[5]

References

^ ^a ^b ^c ^d ^e ^f ^g Terasaka S, Hachiuma K, Mano Y, Onishi K, Kitajima I, Nishino I, Endo H (July 2021). "Drug-drug interaction potential and clinical pharmacokinetics of enerisant, a novel potent and selective histamine H3 receptor antagonist". Xenobiotica. 51 (7): 786–795. doi:10.1080/00498254.2021.1918361. PMID 33910470.
^ ^a ^b Klaus S, Carolan A, O'Rourke D, Kennedy B (September 2022). "What respiratory physicians should know about narcolepsy and other hypersomnias". Breathe (Sheffield, England). 18 (3): 220157. doi:10.1183/20734735.0157-2022. PMC 9973529. PMID 36865656.
^ ^a ^b ^c Inoue Y, Uchiyama M, Umeuchi H, Onishi K, Ogo H, Kitajima I, Matsushita I, Nishino I, Uchimura N (February 2022). "Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials". BMC Psychiatry. 22 (1): 141. doi:10.1186/s12888-022-03785-7. PMC 8862520. PMID 35193545.
^ ^a ^b Alhusaini M, Eissa N, Saad AK, Beiram R, Sadek B (2022). "Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep-Wake Cycle Disorder". Frontiers in Pharmacology. 13: 861094. doi:10.3389/fphar.2022.861094. PMC 9198498. PMID 35721194.
^ ^a ^b Walker NA, Vaughn BV (17 February 2023). "Update on Randomized Controlled Trials in CNS Hypersomnias". Current Sleep Medicine Reports. 9 (2): 101–109. doi:10.1007/s40675-023-00249-6. ISSN 2198-6401.

[pmid33910470-1] ^ ^a ^b ^c ^d ^e ^f ^g Terasaka S, Hachiuma K, Mano Y, Onishi K, Kitajima I, Nishino I, Endo H (July 2021). "Drug-drug interaction potential and clinical pharmacokinetics of enerisant, a novel potent and selective histamine H3 receptor antagonist". Xenobiotica. 51 (7): 786–795. doi:10.1080/00498254.2021.1918361. PMID 33910470.

[pmid36865656-2] Klaus S, Carolan A, O'Rourke D, Kennedy B (September 2022). "What respiratory physicians should know about narcolepsy and other hypersomnias". Breathe (Sheffield, England). 18 (3): 220157. doi:10.1183/20734735.0157-2022. PMC 9973529. PMID 36865656.

[pmid35193545-3] Inoue Y, Uchiyama M, Umeuchi H, Onishi K, Ogo H, Kitajima I, Matsushita I, Nishino I, Uchimura N (February 2022). "Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials". BMC Psychiatry. 22 (1): 141. doi:10.1186/s12888-022-03785-7. PMC 8862520. PMID 35193545.

[pmid35721194-4] Alhusaini M, Eissa N, Saad AK, Beiram R, Sadek B (2022). "Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep-Wake Cycle Disorder". Frontiers in Pharmacology. 13: 861094. doi:10.3389/fphar.2022.861094. PMC 9198498. PMID 35721194.

[Walker_2023-5] Walker NA, Vaughn BV (17 February 2023). "Update on Randomized Controlled Trials in CNS Hypersomnias". Current Sleep Medicine Reports. 9 (2): 101–109. doi:10.1007/s40675-023-00249-6. ISSN 2198-6401.

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