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[Display omitted] This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M 1 (mAChR M 1). Through the continued optimization of M 1 PAM tool compound VU0453595, with a focus on replacement of the 6,7-dihydro-5 H -pyrrolo[3,4- b ]pyridin-5-one with a wide variety of alternative 4,5-dihydropyrrolo-fused heteroaromatics, the generation of M 1 PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M 1 mAChR, and no M 1 agonism. Both compounds have favorable preliminary PK profiles in vitro; 8b additionally demonstrates high brain exposure in a rodent IV cassette model. [ABSTRACT FROM AUTHOR]

• First disclosure of VU6005806/AZN-00016130, an M 4 PAM profiled as a putative candidate. • Novel SAR findings based on novel variations to the C3 position on the pyridazine core. • Minimum effective dose of 0.56 mg/kg po in rat AHL. This letter describes progress towards an M 4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3- c ]pyridazine core has been a consistent feature of key M 4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe. [ABSTRACT FROM AUTHOR]

This Letter details the discovery and subsequent optimization of a novel M 4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M 4 PAM chemotypes. Optimized compounds in this series demonstrated improved M 4 PAM potency on both human and rat M 4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K p = 5.3, K p,uu = 2.4; MDCK-MDR1 (P-gp) ER = 1.1). [ABSTRACT FROM AUTHOR]

[Display omitted] This Letter details our efforts to develop novel tricyclic M 4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3- b ]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3- b :5,4-c′]dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M 4 receptor. [ABSTRACT FROM AUTHOR]

• Discovery of novel 2,3-dimethylimidazo[1,2- a ]pyrazine-6-carboxamide-based M 4 PAMs. • Broad survey of diverse heterocyclic cores. • Balanced human and rat M 4 PAM potency with excellent CNS penetration. This Letter details our efforts to develop new M 4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2 H -indazole-5-carboxamide core or a 1-methyl-1 H -benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4- h ]quinazoline core and an 1-methyl-1 H -[1,2,3]triazolo[4,5- h ]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M 4. [ABSTRACT FROM AUTHOR]

• Discovery of two novel tricyclic-based M 4 PAMs. • Utility of scaffold hopping to improve potency/properties/DMPK. • Balanced human and rat M 4 PAM potency. • Rare 8,9-dimethyl-8 H -pyrazolo[3,4- h ]quinazoline and 1-methyl-1 H -[1,2,3]triazolo[4,5- h ]quinazoline cores. This Letter details our efforts to discover structurally unique M 4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1 H -benzo[ d ][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2- a ]pyrazine-6-carboxamide core that provided improved M 4 PAM activity and CNS penetration. [ABSTRACT FROM AUTHOR]

• Novel 2.4-dimehtylcinnoline-based M 4 PAMs. • Utility of scaffold hopping to improve properties/DMPK. • Balanced human and rat M 4 PAM potency. This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M 4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M 4 PAM activity and improved clearance and protein binding profiles. [ABSTRACT FROM AUTHOR]