PAC-832 is the first drug of its kind. It works by selectively blocking a receptor in the brain called “galanin receptor 1,” or GalR1. The drug has sub-micromolar potency for GalR1 and >30x selectivity over GalR2/3. (2/16)
When administered to mice, PAC-832 significantly improves their memory across multiple different memory tests. (3/16)
PAC-832 also has excellent manufacturability and chemical properties (stability, solubility, etc.), low toxicity, and great pharmacokinetics, including being readily absorbed through the stomach and passing the blood-brain barrier - all less appreciated, but no less critical
PAC-832 is currently undergoing IND-enabling studies and will be the first galanin-targeting drug in 15 years (and first selective GalR1-targeting drug ever) to enter clinical trials. Read more about this drug here: pacepharmaceuticals.com (5/16)
What’s GalR1, and what does it have to do with AD? GalR1 is one of three receptors for a molecule called “galanin,” which acts as a signaling molecule in mammalian brains. Galanin isn’t nearly as well-characterized as other neurotransmitters like dopamine or serotonin, yet it’s
In the 1980s, abnormal galanin signaling was tied to Alzheimer’s through several clinical and scientific observations: (1) brains from deceased AD patients contained many more galanin-producing neurons than normal, concentrated in the basal forebrain - a key memory region in the
These observations led scientists in the 90s to hypothesize that a drug that blocked the action of galanin in the brain could increase ACh levels and improve memory, similar to how acetylcholinesterase inhibitors like the AD drug donepezil work. An initial cohort of peptide
The first small molecule inhibitors of galanin with potential to pass the blood-brain barrier appeared in the early 2000s. A few high-throughput screens were carried out for GalR1 (galanin receptor 1) antagonism by big pharma companies Schering-Plough (now part of Merck) and J&J,
Later in the 2000s, a more complete picture of galanin signaling emerged. New studies showed that galanin surprisingly protected neuronal health in various contexts, suggesting that neurons in AD patients overexpressed galanin to ‘protect’ the neurons from neurotoxic factors
However, the seemingly contradictory harmful vs. protective effects of galanin were soon resolved by molecular research tied to the three galanin receptors, known as GalR1-3. The galanin receptors are part of a large family of receptors known as ‘G-protein coupled receptors,’
On the other hand, GalR2 was found to activate a different G-coupled pathway - the Gq/11 pathway, which broadly results in cell activation. Various studies found that the protective effects of galanin were downstream of this pathway and mediated through GalR2. (12/16)
A viable path for a drug targeting galanin signaling emerged from these findings. Rather than blocking galanin activity across all contexts, one could in theory design an inhibitor that selectively blocks ONLY GalR1 and/or GalR3 (thus removing the brake on ACh release, and
Following this strategy, the GalR3-selective small molecule antagonist HT-2157 was developed by Synaptic Pharmaceutical and entered clinical trials in 2011 for depression. However, the drug did not progress beyond Phase 1 due to safety issues. After that, interest in
My new drug, PAC-832, builds upon decades of progress from the galanin field and solves all the problems that caused previous galanin-targeting drugs to fail. Unlike Sch202596, PAC-832 has great manufacturability - it’s possible to synthesize large quantities of it in a garage
A final word: the development of PAC-832 was catalyzed by various modern technologies, most notably liquid-handling robotics and large language models / AI agents. All of the in vitro screening was performed by an OpenTrons OT-2 liquid-handling robot programmed by Claude Code.