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• 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]

The prefrontal cortex (PFC) integrates information from multiple inputs to exert top-down control allowing for appropriate responses in a given context. In psychiatric disorders such as posttraumatic stress disorder, PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)–dependent long-term depression in the PFC that we hypothesize is involved in appropriate fear responding and could serve to reduce cortical hyperactivity following stress. However, it is unknown whether this long-term depression occurs at fear-related inputs. Using optogenetics with extracellular and whole-cell electrophysiology, we assessed the effect of mAChR activation on the synaptic strength of specific PFC inputs. We used selective pharmacological tools to assess the involvement of M 1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. M 1 mAChR activation induced long-term depression at inputs from the ventral hippocampus and basolateral amygdala but not from the mediodorsal nucleus of the thalamus. We found that systemic M 1 mAChR antagonism impaired contextual fear extinction. Treatment with an M 1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning–conditioned mice. M 1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M 1 mAChR function is required for proper contextual fear extinction. Furthermore, an M 1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M 1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder. [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] In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR 4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M 4 potency, and further structure–activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M 4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration. [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]

[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]

• 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]