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. 2026 Jul 6;17(8):1901–1908. doi: 10.1021/acsmedchemlett.6c00318

Discovery of VU6052959/BI’7927: A Selective mGlu3 Positive Allosteric Modulator (PAM) from an Orthogonal Benzoxazine Chemotype

Caleb A Jones †,‡, Renn A Duncan †,‡, Kristen M Gilliland †,‡, Daniel H Haymer †,‡, Paul K Spearing †,‡, Rory A Capstick †,‡, Bartholomew P Roland †,‡, Paige Vinson †,‡, Marc Quitalig †,‡, Caroline Baggeroer †,‡, Natasha B Billard †,‡, Jonathan W Dickerson †,‡, Katherine J Watson †,‡, Valerie M Kramlinger †,‡, Olivier Boutaud †,‡, Daniel Ursu ∇, Carsten T Wotjak ∇, Henning Priepke ∇, Michel Garneau ∇, Kristina Trenz ∇, Colleen M Niswender †,‡,∥,⊥,#, Hyekyung P Cho †,‡, Jerri M Rook †,‡,⊥, Matthias Freiwald ∇, Riccardo Giovannini ∇, Heiko Sommer ∇, Scott Hobson ∇, P Jeffrey Conn †,‡, Bruce J Melancon †,‡, Craig W Lindsley †,‡,§,#, Carson W Reed †,‡,*
PMCID: PMC13488376  PMID: 42621469

Abstract

We report the discovery of an additional selective metabotropic glutamate receptor subtype 3 (mGlu3) positive allosteric modulator (PAM) tool compound, VU6052959/BI’7927. A high-throughput screening (HTS) campaign identified a selective mGlu3 PAM VU6046180/BI’3690 (7) containing a benzoxazine core (an orthogonal chemotype to previously reported thiophene tool compound VU6053371/BI’8809 (6)). Lead optimization efforts focused on improving PK parameters led to the identification of VU6052959/BI’7927 (8). Orthogonal PAM 8 demonstrated efficacy in a rat novel object recognition task with conservation of our previously determined PK/PD relationship. However, an Ames positive metabolite halted further progression of 8.

Keywords: metabotropic glutamate receptor subtype 3, mGlu3 , positive allosteric modulator, PAM, cognition, metabolism, novel object recognition, pharmacokinetics

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The negative symptoms and cognitive deficits observed with schizophrenia are poorly addressed by current therapeutic strategies, and these shortcomings can contribute to patient noncompliance with medication regimens. − Current research has focused on overcoming these challenges; as a result, metabotropic glutamate receptor 3 (mGlu3) has generated interest as a potential therapeutic target. , Genetic variations in the gene that encodes for mGlu3 (GRM3) are linked to schizophrenia and cognitive dysfunction. − Activation of mGlu3 induces synaptic plasticity, provides neuroprotective effects, and rescues pharmacological disruptions in cognition. − These studies utilized tool compounds 1-5; however, the inclusion of a selective mGlu3 PAM was absent (Figure ). , Recently, we disclosed the discovery and optimization of the first-in-class, selective mGlu3 PAM tool compound 6 containing a thiophene chemotype. While PAM 6 showed efficacy in rat cognition models, the further profiling of 6 in rat exploratory toxicology studies revealed adverse neurobehavioral and clinical findings. In order to determine whether these adverse findings were chemotype-related (i.e., thiophene, a known toxicophore) or mechanism-based, reevaluation of HTS hits was prioritized in order to find an orthogonal chemical species to aid in answering this question.

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Structures of representative selective group II mGlu receptor dual orthosteric mGlu2/3 agonist LY379268 (1), selective mGlu2 negative allosteric modulator (NAM) VU6001966 (2), selective mGlu2 PAM BINA (3), selective mGlu3 NAM VU601576 (4), dual mGlu2/3 PAM VU6023326 (5), and selective mGlu3 PAM VU6053371/BI’8809 (6).

From this exercise, HTS hit VU6046180/BI’3690 (7) was identified (Figure ). In a cAMP assay, 7 was a human mGlu3 PAM (EC50 = 323 nM, 35% Glumax) and was inactive on human mGlu2 (cAMP EC50 > 30 μM). In a receptor-regulated GIRK assay (assessing thallium flux as a surrogate for mGlu3 activation , ) the selective mGlu3 PAM activity confirmed (GIRK human mGlu3 EC50 = 835 nM, 44% Glumax; GIRK human mGlu2 EC50 > 30 μM). Thus, we identified a selective mGlu3 PAM from an orthogonal chemical series. The structure of the benzoxazine core enabled rapid, parallel iterative synthesis of analogs en route to optimization of potency and PK properties.

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Multidimensional chemical lead optimization plan for assessing SAR of different regions of the benzoxazine scaffold.

We envisioned a multipronged approach for the chemical optimization of PAM 7 (Figure ). Through extensive analog generation and SAR analysis (Table S1, see Supporting Information), it was discovered that a 3-fluorophenyl motif on the western portion of the molecule was optimal while aza-heterocycles on the eastern aromatic ring were well tolerated. Through these synthetic exercises, the two enantiomers 8 and 9 were identified (Figure ). Gratifyingly, an enantio-preference was observed, as 8 was discovered to be a potent mGlu3 PAM (human mGlu3 GIRK EC50 = 36 nM, 79% Glumax) while 9 was less active (human mGlu3 GIRK EC50 = 2.5 μM, 52% Glumax). Initially prepared via a chiral supercritical fluid chromatography (SFC) separation of pure racemic material, chiral synthetic routes were developed to unambiguously assign the absolute stereochemistry of the benzoxazine ring along with optimized protocols to deliver gram-scale amounts of 8 to support additional in vitro and in vivo profiling (Scheme ).

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Structure and in vitro pharmacology data for enantiomers 8 and 9.

1. Optimized Chiral Synthetic Route for 8 .

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Chiral amino alcohol 10 was protected with Boc anhydride to afford alcohol 11, which was then reacted with phenol 12 in a Mitsunobu reaction employing ADDP and tributylphosphine ((nBu)3P) to produce intermediate 13. An intramolecular Buchwald-Hartwig coupling furnished Boc-protected benzoxazine 14. Subsequent Boc-deprotection and N-methylation yielded nitro-benzoxazine 15 in excellent yield over two steps. Lastly, nitro reduction followed by immediate acylation of the resulting aniline intermediate with 2-pyrimidinecarbonyl chloride 16 afforded 8 in quantities sufficient for additional in vitro and in vivo profiling.

8 was a mGlu3 PAM for both human (EC50= 36 nM, 79% Glumax) and rat mGlu3 (EC50= 16 nM, 65% Glumax). Importantly, 8 was inactive (EC50 > 30 μM) at both human and rat mGlu2, mGlu1, and mGlu5. PAM 8 displayed good free fraction in both plasma (human and rat f u = 0.04 and 0.04, respectively) and rat brain (BHB f u = 0.01). The predicted hepatic clearance of 8 was also found to be favorable (CLhep (h,r) = 5.7 and 24.9 mL/min/kg, respectively). Additionally, 8 displayed a good CYP450 profile (IC50s: 3A4 (>30 μM), 2D6 (>30 μM), 2C9 (16 μM), 1A2 (>30 μM)). 8 possessed good kinetic aqueous solubility (65 μM at pH = 6.8; 70 μM at pH = 2.2), and high solubility in both FaSSIF (84 μg/mL) and FaSSGF (30 μg/mL). Predicted human CNS penetration in an MDCK-MDR1 assay for 8 was high (P-gp ER = 0.4; Papp = 62 × 10–6 cm/s). In an ancillary pharmacology panel (Eurofins Lead Profiling Screen), displacement of radioligands were observed at human dopamine transporter (DAT) (63% at 10 μM) and human norepinephrine transporter (NET) (66% at 10 μM). Subsequent radioligand binding assays for DAT produced a binding IC50 of 3.9 μM and a Ki of 3.1 μM (affording at least an ∼ 100-fold selectivity window). Additionally, PAM 8 displayed an acceptable in vivo pharmacokinetic profile. In a rat IV/PO PK crossover study, 8 exhibited low clearance (CLp = 19.8 mL/min/kg), as well as moderate half-life (t 1/2 = 0.8 h), moderate mean residence time (MRT = 0.9 h), good volume of distribution (Vss = 1.1 L/kg), and good oral bioavailability (%F = 60%). In a rat IV plasma:brain level (PBL) cassette (0.2 mg/kg, 15 min time point), 8 displayed robust CNS exposure (Kp = 2.4 and Kp,uu = 0.6) (Table ).

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

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a

h = human and r = rat.

Similar to the previous thiophene PAM tool compound 6, we assessed orthogonal PAM 8 in a rat novel object recognition (NOR) assay (Figure ). , At 10 mg/kg PO, robust enhancement in rat recognition memory was observed. At this dose, unbound brain levels of 8 were 50.1 nM (∼3.1-fold the rat mGlu3 PAM EC50). Thus, unbound brain exposures at, or above, the rat mGlu3 PAM EC50 affords a robust PK/PD relationship for efficacy in the NOR paradigm. This is in alignment with what was observed with previous thiophene tool compound 6.

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Novel Object Recognition (NOR) test in male Sprague–Dawley rats with VU6052959/BI’7927 (8). PAM 8 dose-dependently enhanced recognition memory in rats. Pretreatment with 3 (N = 20), 10 (N = 19) and 30 (N = 19) mg/kg 8 (PO, 0.5% natrosol/0.015% Tween 80 in water, 30 min) prior to exposure to identical objects significantly enhanced recognition memory assessed 24 h later. *p < 0.05; **p < 0.01 One-way ANOVA, Dunnett post hoc test.

Next, PAM 8 was assessed for its ability to reverse various pharmacological-induced disruptions in NOR. For these studies, both the NMDA receptor antagonist MK-801 (Figure A) and the muscarinic receptor antagonist scopolamine (Figure B) were chosen as the pharmacological challenges. In both cases, PAM 8 dose-dependently reversed these deficits in rat NOR. Exposure data from rat satellite PK animals correlate well with the aforementioned PK/PD relationship.

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(A) MK-801-induced (0.075 mg/kg, s.c., saline) disruptions in NOR were dose-dependently reversed by PAM 8 (3, 10, and 30 mg/kg 8 PO, 0.5% natrosol/0.015% Tween 80 in water). N = 7–12/group of male Sprague–Dawley rats. ANOVA *p < 0.05; Dunnett post hoc test as compared to vehicle + MK-801 control. (B) Scopolamine-induced (1 mg/kg, i.p., 10% Tween 80) disruptions in NOR were dose-dependently reversed by PAM 8 (3, 10, and 30 mg/kg 8 PO, 0.5% natrosol/0.015% Tween 80 in water). N = 10–12/group of male Sprague–Dawley rats. ANOVA *p < 0.05; Dunnett post hoc test as compared to vehicle + scopolamine control.

To determine if mGlu3 engagement during the familiar object presentation (T1) is necessary to enhance NOR in rat, mGlu3 PAM 8 was administered at 14 or 1 h prior to T1 (30 mg/kg PO). Similar to the data in Figure , animals pretreated with 30 mg/kg of 8 1 h prior to T1 exhibited significantly increased recognition memory compared to vehicle-treated control animals (Figure ). Increasing the pretreatment time for 8 to 14 h prior to T1 significantly attenuated the enhancement of recognition memory when compared to vehicle-treated control animals (Figure ). This indicates that target engagement during familiar object presentation (T1) is required to enhance recognition memory in these animals.

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NOR test in male Sprague–Dawley rats after 14 or 1 h pretreatment with 8. Pretreatment of 14 h with 30 mg/kg 8 did not enhance recognition index (p = 0.30; N = 15). Animals pretreated with 30 mg/kg of 8 1 h before T1 demonstrated enhanced recognition memory when compared to vehicle control animals (**p = 0.005; unpaired t test; N = 14–15). Satellite PK data shows free brain exposure of 8 for this study.

Next, subchronic dosing of 8 was utilized to determine if repeated dosing over 5 days would result in tachyphylaxis or a priming effect of 8 on NOR. The dosing paradigm was performed as shown in Figure and was divided into 5 groups (Group I received vehicle only, Group II received 8 1 h prior to T1, Group III received 8 24 h prior to T1, Group IV received 8 daily for 5 days prior to T1 and 1 h prior to T1, and Group V received 8 daily for 5 days prior to T1 with the last dose 24 h prior to T1). The animals in Group III and V, where the last dose of 8 was 24 h prior to T1, did not demonstrate a significant enhancement of recognition index when compared to Group I (vehicle control animals; Figure ). The animals in Groups II and IV, in which the final or only dose of 8 was administered 1 h prior to T1, demonstrated enhanced recognition index when compared to the Group I control animals (Figure ). There was no significant difference in the recognition index for animals in Group II when compared to Group IV. This indicates that 8 does not exhibit priming or tachyphylaxis in this assay and further demonstrates that sufficient extent of target engagement by 8 at T1 is required to enhance recognition memory in these animals.

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NOR test in male Sprague–Dawley rats after subchronic pretreatment with 8. Animals pretreated 1 h before T1 with 30 mg/kg of 8 demonstrated enhanced recognition memory when compared to vehicle control animals (Group II compared to Group I; *p < 0.05; One-way ANOVA with Dunnett’s Multiple Comparison test; N = 12–14). Similarly, animals pretreated daily for 5 days with 30 mg/kg of 8 and then 1 h prior to T1 exhibited an enhanced recognition index compared to vehicle treated control animals (Group IV vs Group 1; *p < 0.05; N = 13–14). Animals pretreated with 30 mg/kg of 8 24 h prior to T1 did not show enhanced recognition memory compared to vehicle-treated animals (Group III vs Group I; N = 13–14). Similarly, daily dosing of 30 mg/kg of 8 for 5 days with the last dose 24 h prior to T1 did not enhance recognition index compared to vehicle-treated controls (Group V vs Group I; N = 13–14).

We next assessed the well-established metabolic liability of the amide linker within PAM 8, as upon potential amide hydrolysis, electron-rich benzoxazine aniline 17 would be released (Scheme ). Since electron-rich anilines are known structural alerts/toxicophores, it was paramount that this potential metabolite 17 be tested in an Ames assay (both with and without metabolic activation) to assess its mutagenic potential. Unfortunately, electron-rich aniline 17 produced an Ames positive result, precluding further development of 8 as a candidate.

2. Potential Amide Hydrolysis of 8 Would Liberate Electron-Rich Aniline 17 .

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In summary, the discovery of VU6052959/BI’7927 (8), a selective, CNS-penetrant mGlu3 PAM from an orthogonal chemical class is disclosed. PAM 8 was found to be a robust in vivo tool compound with efficacy in rat NOR assays. However, electron-rich aniline 17 (a potential amide hydrolysis metabolite) produced an Ames positive result which led to discontinuation of 8. Progress in rectifying these issues is ongoing and will be reported in due course.

Supplementary Material

ml6c00318_si_001.pdf (513.7KB, pdf)

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.6c00318.

  • Additional experimental details, methods for the synthesis and characterization of all compounds, in vitro and in vivo DMPK protocols, and supplemental tables. All final compounds are >95% pure by HPLC and 1H NMR analysis. (PDF)

C.W.R., C.W.L., B.J.M., P.J.C., C.M.N., V.M.R., O.B., H.P.; S.H. H.S., R.C., M.F. and H.P.C. oversaw the medicinal chemistry, target selection and generated/interpreted biological/DMPK data. C.W.R. and C.W.L. wrote the manuscript. C.W.R., C.A.J., R.A.D., K.M.G., D.H.S., P.K.S., D.H.H., R.A.C. and H.S. performed chemical synthesis. M.M., 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. V.M.K. O.B., M.F. performed in vitro and in vivo DMPK studies. Z.X. performed electrophysiology 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 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.).

Safety Statement: No unexpected or unusually high safety hazards were encountered.

The authors declare the following competing financial interest(s): The authors are actively developing mGlu3 PAMs in collaboration with Boehringer Ingelheim and have filed patents on chemotypes other than that disclosed in this manuscript.

Published as part of ACS Medicinal Chemistry Letters special issue “Allosteric Modulators in Drug Discovery”.

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Supplementary Materials

ml6c00318_si_001.pdf (513.7KB, pdf)

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