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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.

Herein, we report the SAR leading to the discovery of VU6028418, a potent M 4 mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered., Competing Interests: The authors declare the following competing financial interest(s): C.M.N., J.W.D., C.W.L., P.J.C., T.M.B., J.M.R., T.R.C., L.A.B., C.H., M.S., J.L.E., D.W.E., and A.M.B. are inventors on applications for composition of matter patents that protect several series of M4 antagonists., (© 2021 American Chemical Society.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M 4 PAMs and question if the NH 2 group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the β-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH 2 , generating des-amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M 4 PAMs with poor DMPK properties. Cyclization of the β-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M 4 PAMs, many as potent as the classical bicyclic β-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the β-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M 4 PAM activity within classical bicyclic M 4 PAM scaffolds., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu 5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp 3 character, uniform CYP 450 -mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu 5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu 5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu 5 versus DAT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Herein, we report the structure-activity relationships within a series of mGlu 7 PAMs based on a pyrazolo[1,5- a ]pyrimidine core with excellent CNS penetration ( K p s > 1 and K p,uu s > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu 7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.

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.).

Herein, we detail the optimization of the mGlu 2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu 2 NAM scaffold. This new chemotype not only affords potent and selective mGlu 2 inhibition, as exemplified by VU6001966 (mGlu 2 IC 50 = 78 nM, mGlu 3 IC 50 > 30 μM), but also excellent central nervous system (CNS) penetration ( K p = 1.9, K p,uu = 0.78), a feature devoid in all previously disclosed mGlu 2 NAMs ( K p s ≈ 0.3, K p,uu s ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu 2 PET tracer development.

This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Management Case Studies describe approaches to real-life management problems in health systems. Each installment is a brief description of a problem and how it was dealt with. The cases are intended to help readers deal with similar experiences in their own work sites. Problem solving, not hypothesis testing, is emphasized. Successful resolution of the management issue is not a criterion for publication-important lessons can be learned from failures, too.

As institutions continue to expand their drug policy development efforts in order to improve care and reduce cost, the use of multifaceted approaches offer several benefits. Population data on drug use support the need for policy action. The use of institutional outcomes data in conjunction with published evidence augments the process, and the consensus approach to guideline development engenders medical staff support. Such efforts, however, require significant dedication of human resources. Institutions with limited personnel to allocate to drug policy activities may consider increasing the depth of their efforts (using a multifaceted approach) while limiting the breadth of their efforts (only attempting one or two major targets per year, and doing them well).