PF-06827443

Important as an experiment rather than as a drug. Its convulsion finding is the most quoted reason the field decided that intrinsic agonism, not poor subtype selectivity, is the thing that has to be designed out of an M1 compound.

This is the compound the field points at when it says M1 activation carries seizure liability. Pfizer ran dose escalation studies in rats and dogs and found cholinergic adverse events and convulsion at therapeutic indices similar to earlier compounds that had more agonist activity, concluding that positive allosteric modulation of M1 is by itself sufficient to elicit cholinergic adverse events ^[1]. Summarizing that work, the Vanderbilt follow-up states that high doses produced minimal adverse effects in rats while the compound induced severe seizures in dogs ^[2].

That group then gave 100 mg/kg intraperitoneally to mice and saw behavioral convulsions reaching stage 3 on a modified Racine scale in wild type animals and none at all in M1 knockout littermates, which pins the seizure to M1 itself rather than to an off-target effect ^[2]. All of this evidence is preclinical, in rats, dogs and mice. Public trial registries carry no study of PF-06827443 and reviews of the class describe it in preclinical terms only, so what happened to it after these papers, and whether it was ever given to a person, is not documented in the sources available ^[3][4].

PF-06827443 was the lead of a lactam-derived series designed at Pfizer for one specific purpose: to separate allosteric modulation of M1 from allosteric agonism, since the earlier M1 PAMs that caused cholinergic adverse events all carried agonist activity as well ^[1]. The result argued against the hypothesis it was built to test; the molecule caused the same toxicity at the same therapeutic index. In 2018 a Vanderbilt group re-characterized it and showed the premise had been wrong in a second way, because PF-06827443 is a robust ago-PAM once it is examined in other species, at higher receptor reserve and in native tissue rather than in a single low-expressing human cell line ^[2].

Among muscarinic pharmacologists PF-06827443 is a landmark negative result and a useful tool compound, not a candidate anyone still champions. Reviews list it as a Pfizer PAM-agonist with good brain penetrance and procognitive effects in rodents alongside its cholinergic adverse effects ^[4], and the broader class review uses it as one of the cases showing why on-target cholinergic toxicity has repeatedly stopped M1 PAMs ^[3]. It has no profile outside that literature.