Small Molecule · TS-091
Enerisant (TS-091)
Enerisant (developmental code TS-091) is an orally active small-molecule histamine H3 receptor antagonist/inverse agonist designed by Taisho Pharmaceutical and investigated for excessive daytime sleepiness (EDS) in narcolepsy. By blocking presynaptic H3 autoreceptors/heteroreceptors it disinhibits the release of histamine and other wake-promoting neurotransmitters, producing wake-promoting and procognitive effects in rodents. It is a potent and highly selective H3 ligand (human H3 Ki ~1.65 nM; >3,000-fold selectivity over other histamine receptor subtypes and negligible off-target activity). Chemically it is [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone.
Also known as: TS-091, enerisant, 1152747-82-4, [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone
- Modality
- Small molecule
- Chemical class
- pyrazole carboxamide, morpholine, pyrrolidine
- Chemistry
- Single enantiomer
- Mechanism
- H3 receptor Inverse agonist
- Highest phase
- Discontinued
- Lead indication
- Narcolepsy
- Developer
- Taisho Pharmaceutical Co., Ltd.
- Trials
- 1 tracked
Mechanism of action
Enerisant is a potent, highly selective competitive antagonist and inverse agonist at the histamine H3 receptor (HRH3, a class A GPCR). H3 receptors act as presynaptic autoreceptors and heteroreceptors that restrain the release of histamine and other neurotransmitters; by blocking these receptors (and suppressing constitutive H3 signaling), enerisant enhances histaminergic and downstream wake-promoting neurotransmission, producing wake-promoting and procognitive effects in animal models. It binds human H3 with high affinity (Ki ~1.65 nM, pKi 8.8) and inhibits both agonist-stimulated and basal [35S]GTPgammaS binding at human H3, with >3,000-fold selectivity over H1/H2/H4 and negligible off-target activity at dozens of other receptors, transporters and ion channels.
| Target | Action | Affinity |
|---|---|---|
| H3 receptorprimaryHRH3 | Inverse agonist | pKi 8.8ⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Enerisant oral tablet 5, 10, 25, 50, and 100 mg once daily (Phase 2 narcolepsy dose-finding); 5-10 mg once daily in the morning identified as the optimal therapeutic range | Oral | Once daily | — |
Development timeline
- missedBoth Phase 2 fixed-dose trials of enerisant (TS-091) in narcolepsy missed the primary MWT endpoint; the optimal dose could not be determined (efficacy on ESS only at poorly tolerated 25-50 mg doses, while well-tolerated 5-10 mg doses lacked efficacy).↗
- Phase 2 Study 2 (NCT03267303 / JapicCTI-173689) of enerisant 5 and 10 mg/day vs placebo for 3 weeks in narcolepsy (EDS) completed (primary completion 2018-12-13). The primary endpoint (mean sleep latency on MWT) was NOT met: MWT change +0.73 min (5 mg) and +0.66 min (10 mg) vs +0.22 min (placebo); ESS change -4.3 (5 mg, p=0.811) and -3.6 (10 mg, p=0.794) vs placebo. Low doses were well tolerated but lacked efficacy.
- Phase 2 Study 1 (JapicCTI-142529; registered 2014-05-07; 46 randomized; 19 Japanese sites) of enerisant 25/50/100 mg/day vs placebo in narcolepsy (EDS). Primary endpoint (mean sleep latency on MWT) NOT met at any dose: MWT change +0.53 min (25 mg, p=0.380), +0.33 min (50 mg, p=0.263), -0.16 min (100 mg, p=0.594) vs -0.88 min (placebo). ESS (secondary) improved nominally: -8.0 (25 mg, p=0.050) and -8.3 (50 mg, p=0.037) vs placebo, but 25-100 mg doses were poorly tolerated. NOTE: no ClinicalTrials.gov NCT exists for this study (Japic registry only); approximate changed_at used (exact completion date not registered on CT.gov). Captured here because the negative result is tracked deliberately; not loaded as a trials[] row (loader requires an NCT).↗
Enerisant (TS-091) for Narcolepsy
DiscontinuedDiscontinuedNarcolepsy indication →
Taisho Pharmaceutical's narcolepsy program for enerisant (TS-091), a histamine H3 receptor antagonist/inverse agonist targeting excessive daytime sleepiness (EDS), did not advance beyond Phase 2. Two fixed-dose, randomized, double-blind, placebo-controlled Phase 2 trials were conducted: Study 1 (25/50/100 mg/day; JapicCTI-142529; 46 randomized; 19 Japanese sites) and Study 2 (5/10 mg/day; NCT03267303 / JapicCTI-173689; 53 randomized; Japan and Korea). The primary endpoint, mean sleep latency on the Maintenance of Wakefulness Test (MWT), was NOT met versus placebo at any dose in either study. Although the Epworth Sleepiness Scale (secondary) improved nominally at the 25 and 50 mg doses in Study 1, those higher doses were poorly tolerated (insomnia, headache, nausea, frequent withdrawals), while the well-tolerated low doses (5/10 mg) lacked efficacy. The investigators concluded that an optimal dose could not be determined, citing large interindividual variability. Results were published in BMC Psychiatry in February 2022; no further clinical development for narcolepsy has been reported.
Readouts
- 2022-02-22ReportedFull resultsmissedNCT03267303
Both Phase 2 fixed-dose trials of enerisant (TS-091) in narcolepsy missed the primary MWT endpoint; the optimal dose could not be determined (efficacy on ESS only at poorly tolerated 25-50 mg doses, while well-tolerated 5-10 mg doses lacked efficacy). ↗
Clinical trials
NCT03267303JapicCTI-173689Phase 2Completedn=53
A Phase II, Double-blind, Parallel-group Comparative Study 2 of TS-091 in Patients with Narcolepsy
missedprimaryChange from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT) at Week 3 — MWT change +0.73 +/- 3.42 min (5 mg) and +0.66 +/- 3.44 min (10 mg) vs +0.22 +/- 4.90 min (placebo)
Primary endpoint NOT met: neither enerisant 5 mg nor 10 mg once daily significantly improved mean sleep latency on the MWT versus placebo over 3 weeks in patients with narcolepsy.
missedsecondaryChange from baseline in total Epworth Sleepiness Scale (ESS) score at Week 3 (secondary) — ESS change -4.3 +/- 6.8 (5 mg) and -3.6 +/- 4.6 (10 mg) vs placebo (0.811)
Secondary ESS endpoint not significant at the well-tolerated low doses: 5 mg p=0.811 and 10 mg p=0.794 vs placebo. (p_value field shows the 5 mg comparison.)
Identifiers
- PubChem CID 42601503
- FDA UNII E2Y97PQY3A
Sources
- A Study to Evaluate the Safety and Efficacy of TS-091 in Patients With Narcolepsy (Phase II Study 2) — ClinicalTrials.gov
- enerisant | Biological activity (human H3 pKi 8.8) | IUPHAR/BPS Guide to PHARMACOLOGY — IUPHAR/BPS Guide to Pharmacology
- Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials — BMC Psychiatry (Umeuchi et al., 2022)
- Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials (oral, once daily in the morning; 5/10/25/50/100 mg) — PubMed Central (PMC8862520)