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Herein we report progress toward a backup clinical candidate to the M 1 positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3- b ]pyridine-based M 1 PAM VU6007477 to isomeric pyrrolo[3,2- b ]pyridine and thieno[3,2- b ]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2- b ]pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability in vivo screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M 1 PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable in vivo tool compound in rats and nonhuman primates, but not mouse, to study selective M 1 activation.

While the muscarinic acetylcholine receptor mAChR subtype 5 (M 5 ) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M 5 antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, VU6036864 ( 45 ) showed exquisite potency (human M 5 IC 50 = 20 nM), good subtype selectivity (>500 fold selectivity against human M 1-4 ), desirable brain exposure ( K p = 0.68, K p,uu = 0.65), and high oral bioavailability (% F > 100%). VU6036864 ( 45 ) and its close analogues will support further studies of M 5 as advanced antagonist tool compounds and play an important role in the emerging biology of M 5 .

This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M 4 ) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3- b ]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3',2':4,5]thieno[3,2- d ]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2- d ]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M 4 and greatly reduced cytochrome P450 inhibition when compared with parent compound ML253 ., Competing Interests: The authors declare the following competing financial interest(s): R.A.C., S.R.B., J.L.E., M.F.L., C.W.L., P.J.C., T.M.B., D.W.E., and K.J.T. are inventors on applications for composition of matter patents that protect several series of M4 positive allosteric modulators., (© 2024 The Authors. Published by American Chemical Society.)

A scaffold hopping exercise from a monocyclic mGlu 2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu 2 NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu 2 NAM potency, selectivity (versus mGlu 3 and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.

Herein, we report the chemical optimization of a new series of M 1 positive allosteric modulators (PAMs) based on a novel pyrrolo[2,3- b ]pyridine core, developed via scaffold hopping and iterative parallel synthesis. The vast majority of analogs in this series proved to display robust cholinergic seizure activity. However, by removal of the secondary hydroxyl group, VU6007477 resulted with good rat M 1 PAM potency (EC 50 = 230 nM, 93% ACh max), minimal M 1 agonist activity (agonist EC 50 > 10 μM), good CNS penetration (rat brain/plasma K p = 0.28, K p,uu = 0.32; mouse K p = 0.16, K p,uu = 0.18), and no cholinergic adverse events (AEs, e.g., seizures). This work demonstrates that within a chemical series prone to robust M 1 ago-PAM activity, SAR can result, which affords pure M 1 PAMs, devoid of cholinergic toxicity/seizure liability., Competing Interests: The authors declare the following competing financial interest(s): Hold IP on M1 PAMs.

Herein, we detail the optimization of the mGlu 3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu 3 NAM scaffold that engenders potent and selective mGlu 3 inhibition (mGlu 3 IC 50 = 245 nM, mGlu 2 IC 50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma K p = 1.2, K p,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).