A novel series of small molecule TrkB modulators demonstrating potent neuroplastic and antidepressant effects in preclinical models

Background

Pangea Bio is developing the OT-1xx series of orally bioavailable small molecule tropomyosin receptor kinase B (TrkB) modulators for the treatment of mood disorders. Mood disorders represent a significant unmet medical need, with a substantial proportion of patients failing to respond adequately to existing pharmacotherapies. The endogenous ligand of the TrkB receptor is brain-derived neurotrophic factor (BDNF). Physiological BDNF/TrkB signalling is crucial for neuronal and synaptic health. Aberrantly reduced BDNF/TrkB signalling is a hallmark of various mood disorders, where BDNF and TrkB levels are reduced, contributing to synaptic dysfunction and impaired neuroplasticity. The BDNF Val66Met polymorphism, which reduces BDNF secretion and thus TrkB activation, has been associated with increased susceptibility to mood disorders, further implicating the BDNF/TrkB signalling axis as a key biological pathway in mood disorder pathophysiology. Brain-penetrant small molecule TrkB activators therefore offer a compelling therapeutic opportunity, with the potential to restore physiological BDNF/TrkB signalling, promote neuroplasticity, and rescue synaptic dysfunction.

Objectives

To characterise the in vitro pharmacology, CNS drug-like properties, and in vivo efficacy of the OT-1xx series of TrkB modulators in preclinical models.

Methods

In vitro pharmacology was assessed using rat primary neuron assays to investigate neuritogenesis, TrkB pathway activation, and selectivity.

CNS drug properties were assessed in rat pharmacokinetic studies to evaluate oral bioavailability, half-life, and CNS penetration. A single dose (5 mg/kg) of OT-1xx compounds was administered and plasma and brain levels were measured across 24 hours.

In vivo efficacy was evaluated in the chronic social defeat stress model of depression. Male C57BL/6J mice were subjected to repeated social defeat stress over 10 consecutive days through daily encounters with a larger aggressor CD-1 mouse. OT-1xx compounds (1, 3, and 10 mg/kg) were administered orally once daily from Day 11 to Day 34. Fluoxetine (10 mg/kg) served as positive experimental control. Social interaction test (SIT) and forced swim test (FST) were carried out on Days 32 and 33 respectively. Brain and plasma samples were collected on Day 34 for compound exposure analysis. Statistical analysis was performed using one-way ANOVA with Dunnett’s multiple comparison ( p<0.05).

Results

In vitro the OT-1xx series demonstrated potent neuroplastic effects through selective activation of TrkB. When administered orally to rats, OT-1xx compounds exhibited excellent CNS drug properties with high oral bioavailability, long half-life, and high CNS penetration. In the chronic social defeat mouse model of depression, OT-1xx compounds demonstrated significant antidepressant-like efficacy in both the SIT and FST across all doses tested, with dose-dependent increases in brain and plasma exposure.

Conclusions

The OT-1xx compounds demonstrate compelling in vitro pharmacology, CNS drug properties, and in vivo efficacy in a preclinical model of mood disorder. These data support the potential of the OT-1xx series as a novel therapeutic approach to address significant unmet medical needs in mood disorders. Lead compounds from the series are advancing through preclinical development towards clinical studies.

References

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