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. 2025 Feb 5;16(4):745–752. doi: 10.1021/acschemneuro.5c00014

Further Optimization of the mGlu1 PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685

Carson W Reed †,‡, Jacob F Kalbfleisch †,‡, Jeremy A Turkett †,‡, Trevor A Trombley †,‡, Paul K Spearing †,‡, Daniel H Haymer †,‡, Marc Quitalig †,‡, Jonathan W Dickerson †,‡, Daniel J Foster †,‡, Annie L Blobaum †,‡, Olivier Boutaud †,‡, Hyekyung P Cho †,‡, Colleen M Niswender †,‡,∥,⊥,#, Jerri M Rook †,‡, Henning Priepke ∇, Heiko Sommer ∇, Stefan Scheuerer ∇, Daniel Ursu ∇, P Jeffrey Conn †,‡,∥,⊥,#, Bruce J Melancon †,‡, Craig W Lindsley †,‡,§,*
PMCID: PMC11843613  PMID: 39907715

Abstract

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Herein, we report the further chemical optimization of the metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) VU6024578/BI02982816 and the discovery of VU6033685/BI1752. PAM VU6033685/BI1752 was developed through an iterative process wherein, after the furanyl moiety (a potential toxicophore) was replaced by an N-linked pyrazole, a diversity screen identified a quinoline core, which was further truncated to a pyridine scaffold. PAM VU6033685/BI1752 proved to be a potent and selective mGlu1 PAM with efficacy in both amphetamine-induced hyperlocomotion (AHL) and novel object recognition (NOR) with a clear pharmacokinetic–pharmacodynamic (PK/PD) relationship. VU6024578/BI02982816 was efficacious and well tolerated in rats but not dogs, whereas VU6033685/BI1752 elicited adverse events (AEs) in both rats and dogs. These AEs, noted in two distinct mGlu1 PAM chemotypes, cast a shadow on an otherwise promising molecular target to address multiple symptom clusters in schizophrenic patients.

Keywords: metabotropic glutamate receptor subtype 1 (mGlu1), positive allosteric modulator (PAM), cognition, metabolism, amphetamine-induced hyperlocomotion, pharmacokinetics

Introduction

There is a renaissance in CNS drug discovery, and psychiatry in particular, with a quest for fundamentally new targets for the treatment of schizophrenia.1−5 Driven by the approval of Cobenfy (KarXT), an M1/M4 preferring agonist, and the first new mechanism (muscarinic activation) for schizophrenia in decades,6−8 there is a focus on nondopaminergic targets. Following on the heels of Cobenfy comes Cerevel’s Emraclidine, a selective M4 PAM, recently acquired by AbbVie.9 Decades of work on M4 PAMs in our laboratories have demonstrated that the antipsychotic effects of M4 activation, and the ability to inhibit dopamine release, are dependent on coactivation of the metabotropic glutamate receptor subtype 1 (mGlu1); additionally, M4 PAM activity can be blocked by mGlu1 NAMs.10 These data led our group to develop mGlu1 PAMs as a complementary therapeutic strategy to M4 PAMs.11−13 Second-generation mGlu1 PAM tool compounds reversed psychostimulant-induced hyperlocomotion, displayed efficacy in novel object recognition, and improved cognitive performance in a subchronic phencyclidine (PCP) NMDA hypofunction model. Moreover, we demonstrated that mGlu1 PAMs inhibit dopamine release in an endocannabinoid-dependent manner, as do M4 PAMs.11−13 Human genetic data also support mGlu1 as a viable target for schizophrenia, with numerous loss-of-function single nucleotide polymorphisms (SNPs) in GRM1, the gene-encoding mGlu1 in schizophrenia and bipolar patients. Encouragingly, mGlu1 PAMs can rescue signaling of these mutants in vitro.14

Existing mGlu1 PAM tool compounds 1 and 2 (Figure 1) were acceptable for in vivo target validation studies, but they lacked drug-like profiles to advance.15−24 Hence, we recently reported on a novel mGlu1 PAM, VU6024578/BI02982816 (compound 3) that displayed robust efficacy in rodent models of antipsychotic-like activity and cognition, with a clear PK/PD relationship and a path forward with a biomarker strategy.25 However, the naked furanyl moiety, as a potential toxicophore and unexpected adverse events (AEs) observed in dogs, led to the termination of 3. Were the AEs chemotype-driven, or could they be due to unfavorable signal bias or activity at an mGlu1/mGlu5 heterodimer? Here, we describe a lead optimization campaign that identified a replacement for the undesired furanyl moiety and resulted in the discovery of a fundamentally new chemotype, exemplified by VU6033685/BI1752. With a new mGlu1 PAM in hand, we disclose the full characterization (molecular pharmacology, in vitro and in vivo DMPK, and behavioral) of VU6033685/BI1752, as well as more egregious AEs in both rats and dogs, casting a shadow on a promising schizophrenia target.

Figure 1.

Figure 1

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Structures of exemplar in vitro and in vivo mGlu1 PAM tool compounds 1–3.

Results and Discussion

Chemical Lead Optimization

The chemical optimization plan for 3 was based on a multidimensional strategy (Figure 2) to ultimately develop a distinct chemotype from 3 to assess the AEs observed in dogs with VU6024578/BI02982816 to understand mechanism-based or chemotype-based effects.25 At the same time, we had to identify an alternative for the naked southern furanyl moiety, a known toxicophore.26 In parallel, efforts examined alternatives for the western pyrazole, as well as the furanyl moiety (Figure 3). SAR was steep when surveying alternatives for the western pyrazole, but regioisomeric 4 was identified with enhanced potency (human EC50 = 28 nM, 72% Glu Max) over 3. PAM 4 was also potent on rat mGlu1 (EC50 = 37 nM, 137% Glu Max), with good unbound fraction in plasma (fu (h, r) = 0.063, 0.040) and brain (fu (rat) = 0.044), CNS penetration (Kp = 0.89, Kp,uu = 0.98), clean CYP450 profile (>30 μM at 3A4, 2D6 and 2C9; 14.7 μM at 1A2), and moderate predicted hepatic clearance (CLhep (h, r) = 15.1 mL/min/kg and 34.2 mL/min/kg).27 However, these positive attributes did not address the liability of the furanyl ring. A broad survey of 5- and 6-membered heterocycles identified a single alternative for the furanyl ring, an N-linked pyrazole, 5. While an order of magnitude less potent (human mGlu1 EC50 = 551 nM, rat mGlu1 EC50 = 558 nM, 105%) than 3, the overall DMPK profile was far more attractive. PAM 5 displayed low predicted hepatic clearance (CLhep (h, r) = 4.6 mL/min/kg and 21.4 mL/min/kg), high unbound fraction in plasma (fu (h, r) = 0.143, 0.095) and brain (fu (rat) = 0.185), and an exceptional CYP450 inhibition profile (>30 μM at 3A4, 2D6, 2C9, and 1A2). CNS penetration in rat (Kp = 0.3, Kp,uu = 0.52) was lower than 3, but in vivo rat IV/PO PK was improved (CLp = 2.9 mL/min/kg, t1/2 = 3 h, Vss = 0.63 L/kg; 45.7% F).27 Thus, we elected to maintain the N-linked pyrazole in a fragment screening approach to identify alternative amides for the western bis-pyrazole moiety and hopefully improve the mGlu1 PAM functional potency.

Figure 2.

Figure 2

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Envisioned, multidimensional chemical optimization plan for mGlu1 PAM 3.

Figure 3.

Figure 3

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Chemical optimization plan for mGlu1 PAM 3, leading to the identification of novel pyrazole regioisomer 4 (EC50 = 28 nM, 72% Glu Max) and N-linked pyrazole 5 (EC50 = 527 nM, 76% Glu Max) as an alternative for the furanyl ring.

A large scan of various heteroaryl methyl amines and benzyl amines was coupled to the requisite N-pyrazole linked benzoic acid; however, the vast majority of analogs proved to be weak or inactive mGlu1 PAMs. Two quinoline-derived amide analogs, 6 (EC50 = 32 nM, 56% Glu Max) and 7 (EC50 = 17 nM, 56% Glu Max), proved to be very potent mGlu1 PAMs, albeit with modest efficacy (Figure 4). In the case of 7, this represented an ∼31-fold increase in the mGlu1 PAM potency over 5. While 6 was more potent than 5, it possessed a poor in vitro DMPK profile (CLhep (h, r) = 15.8 mL/min/kg and 47.8 mL/min/kg; plasma fu (h, r) = 0.037, 0.054; brain fu (r) = 0.047; CYP450 inhibition: (IC50s = 8.8 μM (3A4), 6.9 μM (2D6), 6.4 μM (2C9), and 15.9 μM (1A2)) and was clearly not advanceable.27 However, we wanted to examine in vivo rat IV/PO PK to fully assess this novel chemotype and establish if an in vitro:in vivo correlation (IVIVC) existed. For 6, an attractive rat in vivo PK profile (CLp = 15.3 mL/min/kg, t1/2 = 1.1 h, Vss = 1.64 L/kg; 64% F, 30 min Tmax) was observed, but with a lack of IVIVC. Finally, this new chemotype was predicted to be CNS penetrant in man (P-gp, MDCK-MDR1 ER = 0.5, Papp = 39 × 10–6 cm/s). The analogous 8-fluoro congener 7 possessed even greater mGlu1 PAM activity (EC50 = 17 nM, 56% Glu Max), and we hoped that the electronegative fluorine might improve the CYP450 profile. Unfortunately, the 8-F moiety had limited impact on the CYP450 profile (IC50s = 9.0 μM (3A4), > 30 μM (2D6), 5.9 μM (2C9), and 11.2 μM (1A2)), and the in vitro disposition (CLhep (h, r) = 13.3 mL/min/kg and 46.8 mL/min/kg; plasma fu (h, r) = 0.053, 0.016; brain fu (r) = 0.040) was similar to 6. However, the rat in vivo profile did improve (CLp = 8 mL/min/kg, t1/2 = 2.1 h, Vss = 1.0 L/kg, and Kp = 0.98).27 Thus, while not optimal, the effort to identify a chemically distinct mGlu1 PAM is moving in the right direction.

Figure 4.

Figure 4

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Fragment library amide scan for the chemical optimization of mGlu1 PAM 5, leading to the identification of novel quinoline amides 6 (EC50 = 32 nM, 56% Glu Max) and 7 (EC50 = 17 nM, 56% Glu Max) as alternatives for bis-pyrazole ring system.

Having experienced DMPK challenges with quinolines in the past, we elected to truncate the quinoline core to a pyridine core and surveyed a variety of pyridyl methyl amides (Figure 5). This exercise proved highly effective, leading to the discovery of PAM 8 (EC50 = 39 nM, 65% Glu Max), which addressed the in vitro and in vivo DMPK liabilities (CYP450 profile, predicted hepatic clearance, protein binding, etc.) of 6 and 7 and appeared advanceable. The potency of 8 represented an ∼14-fold improvement over 5 and replaced both the furanyl moiety as well as the bis-pyrazole ring system, affording a chemically distinct mGlu1 PAM for in-depth profiling.

Figure 5.

Figure 5

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Truncation and simplification of quinoline amides 6 and 7 to a pyridine core provided 8 (EC50 = 32 nM, 56% Glu Max), a chemically distinct mGlu1 PAM for further profiling.

Chemical Synthesis

The syntheses of novel mGlu1 PAMs 4–8 were straightforward and employed readily available starting materials. For the synthesis of the pyrazole regioisomer 4 (Scheme 1), we employed an advanced intermediate 9, previously described in the synthesis of 3, and performed a Suzuki coupling with boronic ester 10.27 While the yield was low (10%), this afforded sufficient material for evaluation.

Scheme 1. Synthesis of VU6026104 (4).

Scheme 1

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Reagents and conditions. (a) Pd(dppf)Cl2, Na2CO3, 1,4-dioxane:H2O (3:1), 100°C, 2 h, 10%.

For the synthesis of the N-linked pyrazole 5 (Scheme 2), we utilized commercial boronic acid 11 in a copper-catalyzed Chan–Lam coupling28 with 1H-pyrazole. This led to, after saponification, the production of N-linked pyrazole 12 in 52% yield for the two steps. Finally, a HATU-mediated amide coupling with the previously described bis-pyrazole amine 13 delivered 5 in 28% yield.27

Scheme 2. Synthesis of VU6026095 (5).

Scheme 2

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Reagents and conditions. (a) Cu(OAc)2, pyrazole, pyridine, DMF, 70°C, 2h, 58%; (b) NaOH, THF:MeOH:H2O, rt, 18 h, 89%; (c) HATU, DIEA, DMF, 0°C to rt, 28%.

Quinoline analogs 6 and 7 were prepared in a single step (Scheme 3) from commercial amines 14 and 15, via a HATU-mediated amide coupling reaction with 12 to provide 6 and 7, respectively, in yields of ∼40%. Finally, mGlu1 PAM 8 was prepared according to Scheme 4. Starting from commercial aldehyde 16, conversion to the corresponding oxime, followed by Zn-mediated reduction and conversion to the bis-HCl salt afforded the pyridyl methyl amine 17 in 92% yield over the three steps. Then, a HATU-mediated coupling reaction between 17 and acid 12 gave 8 in 67% isolated yield.27

Scheme 3. Synthesis of VU6028266 (6) and VU6030257 (7).

Scheme 3

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Reagents and conditions. (a) 12, HATU, DIEA, DMF, 0°C to rt, 43% for 6 and 37% for 7.

Scheme 4. Synthesis of VU6033685/BI1752 (8).

Scheme 4

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Reagents and conditions. (a) NH2OH·HCl, NaOAc, EtOH, rt, 2 h; (b) Zn, AcOH, rt, 4 h; (c) HCl, 92% over three steps; (d) 12, HATU, DIEA, DMF, 0°C to rt, 67%.

Molecular Pharmacology and DMPK Profile of 8

The novel mGlu1 PAM 8 was a potent PAM across species (human EC50 = 39 nM, 65% (n= 9); rat EC50 = 107 nM, 109% Glu Max (n =7); mouse EC50 = 52 nM, 102% (n= 3); dog EC50 = 93 nM, 79% (n = 3)) and selective (>10 μM at mGlu2–4, 7,8) while a very weak mGlu5 PAM (EC50 = 3,760 nM, 72%).27 From our experience with mGlu5 PAMs, this was a potency value that would not interfere with evaluating selective mGlu1 activation.29 In terms of physicochemical properties (Table 1), PAM 8 displayed acceptable solubility (>100 μM @ pH2.2, < 1.0 μM @pH6.8, FASSGF (572 μg/mL) and FASSIF (23.6 μg/mL)) at neutral pH and exceptional solubility under acidic conditions. Unlike 4-7, PAM 8 demonstrated an attractive, and advanceable, in vitro DMPK profile (CLhep (h, r, d, c) = 9.9 mL/min/kg, 46.7 mL/min/kg, 15.1 mL/min/kg, 33.2 mL/min/kg; plasma fu (h, r, d, c) = 0.063, 0.097, 0.099, 0.46; brain fu (r) = 0.062 and CYP450 inhibition (IC50s = 23.8 μM (3A4), > 30 μM (2D6), 22.3 μM (2C9) and 26 μM (1A2)). PAM 8 was predicted to be highly CNS penetrant in humans, with MDCK-MDR1 ER = 0.93, Papp = 42 × 10–6 cm/s, and was found to be highly CNS penetrant in rats (Kp = 1.8; Kp,uu = 1.2). Rat in vivo PK was favorable (CLp = 26.4 mL/min/kg, t1/2 = 2.1 h, Vss = 5.1 L/kg; 42.8% F, 30 min Tmax).27 Thus far, the profile of 8 warranted further progression down the lead optimization flowchart and into behavioral pharmacology assessment.

Table 1. Pharmacology and In Vitro and In Vivo DMPK Profile of 8.

graphic file with name cn5c00014_0013.jpg

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Behavioral Pharmacology of 8

As PAM 3 reversed amphetamine-induced hyperlocomotion (AHL), a standard preclinical psychosis model where both M4 PAMs and clinically available antipsychotic drugs display robust efficacy; at unbound brain levels at ∼0.7-fold the rat mGlu1 EC50, we evaluated 8 in this paradigm employing 3 as a positive control (Figure 6).25 Here, administration of 0.75 mg/kg of amphetamine subcutaneously (SC) induced a robust hyperlocomotive state in rats (>1800 beam breaks), which was dose-dependently reversed by oral administration of 8. Satellite rat PK taken at the 2.5 h end of study time point showed that at the 10 mg/kg minimum effective dose (MED), there was a free brain concentration of 79.8 nM (∼0.74-fold the in vitro EC50 of 107 nM). Moreover, PAM 8 was of comparable efficacy to the standard 3.27

Figure 6.

Figure 6

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Rat amphetamine-induced hyperlocomotion and reversal by VU6033685 (8). Amphetamine (0.75 mg/kg SC) induced robust hyperlocomotion, which was dose-dependently reversed by oral administration (0.5% Natrasol/0.015% Tween 80) of 8. A clear PK/PD relationship with efficacy was noted at ∼0.7-fold the in vitro rat mGlu1 EC50 in unbound brain, in agreement with the control, VU6024578 (3).

Based on our previous work with mGlu1 PAMs,25 we next evaluated 8 for its ability to reverse MK-801 disruptions of novel object recognition (NOR) in rats (Figure 7). While not as robust as PAM 3, 8 did dose-dependently reverse the deficits induced by MK-801. Exposures with this vehicle (0.5% Natrasol/0.015% Tween 80 in water) at the 30 mg/kg dose achieved free brain levels ∼5.2-fold the rat in vitro EC50 (579 nM).27

Figure 7.

Figure 7

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Rat MK-801-induced disruption of novel object recognition and reversal by VU6033685 (8). MK-801 (0.075 mg/kg SC) induced a robust disruption of NOR, which was dose-dependently reversed by oral administration (0.5% Natrasol/0.015% Tween 80 in water). N = 12–15/group of male Sprague–Dawley rats. One-way ANOVA: p = 0.13.

Dopamine Release

Previously, with PAMs 1 and 2, we demonstrated that activation of mGlu1 reduces striatal DA release via activation of CB2 cannabinoid receptors.11 To confirm that the structurally distinct mGlu1 PAM 8 has a similar effect on dopamine (DA) release, we determined the effect of 8 on a subthreshold concentration of the Group I mGlu agonist DHPG (10 μM). Application of 10 μM DHPG alone did not produce a significant inhibition of striatal DA release. However, this subthreshold concentration of DHPG induced a robust inhibition of DA release (Figure 8) when coapplied with PAM 8 (10 μM). These results suggest that activation of mGlu1 inhibits stimulus-induced DA release in the striatum for multiple mGlu1 PAM chemotypes.27

Figure 8.

Figure 8

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mGlu1-mediates DHPG induced Reductions in Striatal DA Release via PAM 8. Effects of 10 μM DHPG, a group I mGlu receptor agonist, in the absence or presence of 10 μM PAM 8 on electrically evoked striatal DA release. All experiments were performed in the presence of nAChR antagonist (1 μM DHβE). N = 5–6 slices per condition (slices were made from 5 separate mice).

The Emergence of Adverse Events (AEs)

At this point, the project team was focused on derisking a novel mGlu1 PAM chemotype and assessing if the AEs observed with 325 would be noted with 8. For many CNS targets, mice are more sensitive to overstimulation than rats. Thus, we performed a dose escalation PO PK study in mice (50, 150, and 500 mg/kg) with PAM 8 (mouse EC50 = 52 nM, 102%), and achieved >24-fold the EC50 free brain concentration (∼1250 nM) without any observed AEs. At the 500 mg/kg dose, ∼90-fold mouse free brain concentration was achieved, and all animals displayed uncoordinated movements and were cold to the touch. Thus, we initiated a three-day dose escalation toxicology study in mice at doses of 50, 200, and 400 mg/kg with six male mice per dose group to explore AEs above the anticipated human Cmax of 4 μM and AUCss of 62 μM·h. At 50 mg/kg (AUCss of 5.5 μM·h, 0.09 multiple of AUC), there were no test-item-related findings. At 200 mg/kg (AUCss of 69.9 μM·h, 1.1 multiple of AUC), some of the mice showed signs of weight loss, decreased motor activity, and swaying gait. In the high-dose group (500 mg/kg, AUCss of 208 μM·h, 3.4 multiple of AUC), several mice displayed weight loss, decreased motor activity, and swaying gait. Overall, a maximum tolerated dose (MTD) from this study was not reached. Turning our attention back to the rat, we had noted in the NOR study that free brain concentrations up to 5.3-fold the rat EC50 were well tolerated. However, subsequent PO PK studies that reached 6.2-fold the rat EC50 free in brain (664 nM) resulted in piloerection, slow movement, and reaction to stimuli which persisted for ∼2 h postdose. This was surprising, as PAM 3 only exhibited AEs in dogs.25 To assess potential AEs in dogs, we performed a single, low-dose (0.5 mg/kg) IV bolus of PAM 8 to male beagle dogs. PAM 8 possessed a good PK profile in dogs (CLp = 10 mL/min/kg, t1/2= 6.5 h, Vss = 4.6 L/kg); however, all dogs displayed dizziness, salivation, and uncoordinated movements. Combined, these data halted further progression of VU6033685/BI1752 (8) and required the team to pause and postulate the origins of these AEs with mGlu1 PAMs.

Conclusions

In summary, we disclose the further optimization of metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) VU6024578/BI02982816 (3) and the discovery of a chemically distinct mGlu1 PAM, VU6033685/BI1752 (8), to evaluate efficacy and tolerability. PAM 8 was potent, selective, CNS penetrant, and efficacious in both AHL and NOR. Importantly, the furanyl moiety (a potential toxicophore) of 3 was replaced by an N-linked pyrazole in 8. Unlike PAM 3, AEs with 8 were noted not only in dogs but also in mice and rats, which precluded further advancement. The mGlu1 PAM mechanism has strong human genetic support and robust efficacy in preclinical models of psychosis and cognition; however, the origins of the AEs are unclear. Are they target mediated? Like mGlu5 PAMs, is signal bias the key to avoiding AEs? Could the activation of an mGlu1/mGlu5 heterodimer be responsible for the AEs? The project team once again shifted resources to evaluate a third distinct chemotype while delving into a deeper mechanistic exploration of mGlu1 activation. Progress toward these possible origins of the AEs will be reported in due course.

Acknowledgments

The authors thank William K. Warren, Jr. and the William K. Warren Foundation for support of our programs and endowing both the Warren Center for Neuroscience Drug Discovery and the William K. Warren, Jr. Chair in Medicine (C.W.L.) as well as Zoe K. Bryant for her assistance with these studies.

Glossary

Abbreviations

PAM

positive allosteric modulator

PBL

plasma/brain level

DMPK

drug metabolism and pharmacokinetics

AE

adverse event

mGlu1

metabotropic glutamate receptor subtype 1

MED

minimum effective dose

NOR

novel object recognition

AHL

amphetamine-induced hyperlocomotion

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.5c00014.

  • Additional experimental details, methods for the synthesis and characterization of all compounds (1H and 13C NMR, HPLC), in vitro and in vivo DMPK protocols and supplemental figures (PDF)

Author Contributions

C.W.L., B.J.M., P.J.C., C.M.N., J.M.R., A.L.B., O.B., H.P., D.U., S.S. and H.P.C. oversaw the medicinal chemistry, target selection and generated/interpreted biological/DMPK data. C.W.L. and C.W.R. wrote the manuscript. C.W.R., J.J.K., J.A.T., T.A.T., F.K.N., P.K.S., D.H.H. and H.S. performed chemical synthesis. M.D.Q., M.S., H.P.C. and C.M.N. performed in vitro pharmacology assays. J.W.D. and J.M.R. performed in vivo behavior pharmacology assays and in vivo DMPK. S.S., A.L.B. and O.B. performed in vitro and in vivo DMPK studies. D.J.F. performed dopamine release work. All authors have given approval to the final version of the manuscript.

Studies were supported by NIH (NIMH, R01MH119673) and Boehringer Ingelheim (UNIV60533).

The authors declare no competing financial interest.

Supplementary Material

cn5c00014_si_001.pdf (281.8KB, pdf)

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