BNC-375 / Merck (MSD), Neuphoria Therapeutics - LARVOL DELTA

Positive allosteric modulators of the α7 nAChR for the treatment of cognitive disorders: Invention of MK-4334 (ACS-Fall 2026) - "Their leading molecule, BNC375, demonstrated robust efficacy in preclinical cognition models across a broad (>100x) exposure range but suffered several liabilities that precluded further advancement. Ultimately, this work led to the identification of MK-4334, a novel, highly potent, orally bioavailable α7 nAChR PAM with an excellent overall profile and a low projected human dose. MK-4334 was advanced to clinic where it was well-tolerated in multiple Ph 1 studies and demonstrated modulation of a novel translational biomarker of glutamate metabolism via magnetic resonance spectroscopy (MRS) in healthy individuals as proof of biology (POB)."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Developmental Disorders • CHRNA7

A Novel Biomarker of Neuronal Glutamate Metabolism in Nonhuman Primates Using Localized H-Magnetic Resonance Spectroscopy: Development and Effects of BNC375, an α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator. (PubMed, Biol Psychiatry Cogn Neurosci Neuroimaging) - "This study demonstrates that the ratio of C-Glx H3:H4 labeling is a biomarker that may provide an objective readout of compounds affecting glutamatergic neurotransmission and could improve decision making for the development of therapeutic agents."

Biomarker • Journal • Cognitive Disorders

Pharmacological characterization of the novel and selective α7 nicotinic acetylcholine receptor positive allosteric modulator BNC375. (PubMed, J Pharmacol Exp Ther) - "In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in CNS diseases with cognitive impairments."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Psychiatry • Schizophrenia

New treatment for Alzheimer's sufferers (Yahoo News) - "Adelaide-based Bionomics has developed a compound, known as BNC375, which has shown in pre-clinical trials to improve cognitive impairment associated with Alzheimer's and Parkinson's disease in rats and mice. The new therapy will now be developed by US drug giant Merck after it signed a multi-million dollar agreement with Bionomics, believed to be one of the largest ever deals by an Australian biotech firm."

Licensing / partnership • Preclinical • Parkinson's Disease

"Bionomics and MSD Scientists Publish Preclinical Findings for BNC375 in Peer-Reviewed Journal https://t.co/sieWBukSvC" (,@NewsFromBW)

Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of α7 nAChRs. (PubMed, ACS Med Chem Lett) - "Further fine control over the kinetics has been achieved by changing the substitutions on the aniline ring: generally the substitution of aniline with strong electron withdrawing groups reduces the Type II character of these compounds. Our structure-activity optimization efforts have led to the discovery of BNC375, a small molecule with good CNS-drug like properties and clinical candidate potential."

Journal

"BNC-375 analogues as alpha7 nAChR positive allosteric modulators from @Merck for treating Alzheimer's disease. Live from #ACSOrlando" (,@Cortellis)

Discovery of a novel α7 nAChR positive allosteric modulator for the treatment of cognitive disorders (ACS-Sp 2019) - "...The previous lead molecule, BNC375, demonstrated robust efficacy in preclinical cognition models across a wide exposure range and had a good overall profile, but had suboptimal physicochemical properties and a relatively high projected clinical dose. Lead optimization efforts were guided by CNS multi-parameter optimization scoring and resulted in significant improvements to the pharmacokinetics, off-target selectivity profile, and physicochemical properties of the series. Ultimately, this work led to the identification of a novel, highly potent, orally bioavailable α7 nAChR PAM with an excellent overall profile and a low projected clinical dose."