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. 2017 Sep 1;8(10):1110–1115. doi: 10.1021/acsmedchemlett.7b00317

Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines

Masahito Abe †,∥, Mabel Seto †,∥, Rocco G Gogliotti †,∥, Matthew T Loch †,∥, Katrina A Bollinger ∥, Sichen Chang ∥, Eileen M Engelberg †,∥, Vincent B Luscombe †,∥, Joel M Harp §, Michael Bubser †,∥, Darren W Engers †,∥, Carrie K Jones †,∥,‡, Alice L Rodriguez †,∥, Anna L Blobaum †,∥, P Jeffrey Conn †,∥,‡, Colleen M Niswender †,∥,‡,*, Craig W Lindsley †,∥,‡,*
PMCID: PMC5641958  PMID: 29057060

Abstract

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Herein, we report the structure–activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.

Keywords: Positive allosteric modulator (PAM), metabotropic glutamate receptor 7 (mGlu7), cognition, VU6005649, Rett syndrome

Of the eight metabotropic glutamate receptors (mGlus) and their associated three groups (Group I, mGlu1,5; Group II, mGlu2,3; Group III, mGlu4,6,7,8), mGlu7 and mGlu8 remain the least explored due to a lack of selective small molecule tools.1,2 Of these, mGlu7 has emerged as an attractive therapeutic target for anxiety, depression, epilepsy, and schizophrenia based on data from mGlu7 knockout (KO) mice.3−11 Human genetics has further strengthened these associations, with GRM7 polymorphisms linked to schizophrenia, depression, ADHD, and autism.12−23 Additionally, whole exome sequencing approaches have recently identified mutations in the GMR7 gene in patients with previously diagnosed neurodevelopmental disorders.8,23−25 Finally, we have recently described dramatic reductions in mGlu7 protein expression in the brains of patients diagnosed with Rett syndrome (RTT),26 as well as mice modeling the disorder, and have shown that nonselective positive allosteric modulators (PAMs) with mGlu7 activity can correct apneas as well as numerous impaired cognitive and social domains in mice modeling RTT.26

mGlu7 is broadly expressed in the CNS where it critically modulates synaptic transmission and neuronal function.1 Due to a lack of mGlu7-selective small molecule tools, recent efforts, including our own, have employed a nonselective, pan-Group III mGlu receptor (PAMs) in combination with synaptic localization studies, mGlu7 negative allosteric modulators (NAM), and/or Grm7–/– mice to “isolate” selective mGlu7 activation.23,27 As shown in Figure 1, all PAM ligands reported to date are not selective for mGlu7 (e.g., 1 is an mGlu4/8 PAM and both 2 and 3 are pan-mGlu4/7/8 PAMs), while 4 is a selective mGlu7 NAM.1,2,26−29 Thus, our lab initiated a campaign to discover and optimize selective and CNS penetrant mGlu7 PAMs for target validation studies. Here, we detail a new high-throughput screening (HTS) campaign that identified a novel series of pyrazolo[1,5-a]pyrimidines as mGlu7-preferring and dual mGlu7/8 PAMs with excellent CNS penetration and in vivo efficacy in a mouse contextual fear conditioning model.

Figure 1.

Figure 1

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Structures of reported Group III mGlu receptor allosteric ligands. ADX88178 (1) is an mGlu4/8 PAM, VU0155094 (2) is a pan-Group III (mGlu4/7/8) PAM, VU0422288 (3) is a potent pan-Group III (mGlu4/7/8) PAM, and ADX717743 (4) is a selective mGlu7 NAM. No mGlu7 selective or preferring PAMs have been disclosed to date. Potencies were determined in-house.

We performed an HTS campaign on a collection of 63,000 small molecules and identified 438 hits as mGlu7 PAMs in a single-point screen.2 After single-point hit confirmation, counter-screening against untransfected HEK cells, and full concentration–response curve confirmation, 98 compounds were confirmed as mGlu7 PAMs. Hits with attractive chemotypes were then evaluated against mGlu4 and mGlu8; HTS hit 5 (Figure 2), based on a pyrazolo[1,5-a]pyrimidine core, proved worthy of further attention. Hit 5 was selective for mGlu7 (mGlu7 EC50 = 3.3 μM, pEC50 = 5.48 ± 0.14, 104 ± 5 L-AP4 Max mGlu4 EC50 > 10 μM, mGlu8 EC50 > 10 μM) and displayed exceptional CNS penetration (rat plasma/brain Kp = 1.4, Kp,uu = 1.1). From an optimization standpoint, 5 was also attractive in that multiple domains could be surveyed in parallel.

Figure 2.

Figure 2

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Structure of HTS hit 5 (VU6004502), and the four domains to be investigated in the course of the lead optimization campaign.

The synthesis of 5 and related analogues 9 was straightforward (retaining the CF3 moiety) and required only two steps from known materials (Scheme 1) when the requisite boronic acid was commercial.30 In other cases, the desired coupling partner (either aryl boronic acid or aryl stannane 11) was prepared from the corresponding commercial aryl bromides 10. However, this streamlined strategy hinged on a successful condensation of 6 and 7 to form 8 as a single regioisomer. Fortunately, the condensation afforded a single product 8, and single X-ray crystallography30 confirmed the correct regioisomer was obtained (insert). Subsequent Suzuki or Stille cross- coupling of 8, with partners 11, generated analogs 9 in moderate yields. To explore alternatives for the CF3 moiety, additional chemistry was required (Scheme 2).30 Here, a related condensation between 12 and 7 provided a single regioisomer 13, which smoothly underwent cross-coupling reactions to deliver 14. Treatment with POCl3 gave the key chloro derivative 15 that could be diversified via either SNAr reactions to introduce amines 16 and ethers 17 or palladium-catalyzed organozinc chemistry to introduce either a nitrile 17 or cycloalkyl moieties 18 in good yields. All final compounds were >98% pure.

Scheme 1. Synthesis of Analogues 9.

Scheme 1

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Reagents and conditions: (a) EtOH, mw, 110 °C, 30 min, 56–76%; (b) ArB(OR)2, 10 mol % Pd(dppf)Cl2, Cs2CO3, dioxane–water, mw, 150 °C, 30 min, 44–55% or ArSnBu3, 5 mol % Pd(PPh3)4, PPh3, CuBr, LiCL, dioxane, mw, 120 °C, 3 h, 38–42%; (c) bis-pinacolborate, 5 mol % PdCl2(PPh3)2, KOAc, dioxane, 100 °C, 16 h, 50–58% or n-BuLi, Bu3SnCl, THF, 0 °C, 30 min, 84–93%.

Scheme 2. Synthesis of Non-CF3 Analogues 16, 17, 18, and 19.

Scheme 2

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Reagents and conditions: (a) 4-bromo-3-methyl-1H-pyrazol-5-amine, AcOH, mw, 110 °C, 30 min, 68%; (b) ArB(OR)2, 10 mol % Pd(dppf)Cl2, Cs2CO3, dioxane–water, mw, 150 °C, 30 min, 26–38%; (c) POCl3, reflux, 30 min, 61–70%; (d) HNR1R2, EtOH, rt, 2h, 46–56%, or NaOR, ROH, rt, 30 min, 86–97%, or Zn(CN)2, 5 mol % Pd(PPh3)4, NMP, 110 °C, 5 h, 53–75%, or (cycloalkyl)ZnCl, 5 mol % Pd(PPh3)4, THF, reflux, 3 h, 74–83%.

Evaluation of all of these analogues in our functional mGlu7 assay highlighted extremely steep structure–activity relationships (SARs), with the vast majority of the 100 analogues prepared devoid of mGlu7 PAM activity (Figure 3). Both the 7-CF3 and 5-CH3 moieties in 5 proved essential for mGlu7 PAM activity, as all other substituents were inactive (mGlu7 EC50s > 10 μM). The 2-CH3 could be replaced with an ethyl moiety in 5, but all other substituents lost mGlu7 PAM activity. Thus, the only productive SAR resulted from functionalized aryl moieties in analogues 9, where once again the “fluorine walk” strategy2 for allosteric modulator optimization proved fruitful (Table 1). Moreover, all analogues 9 evaluated for CNS penetration in the context of the broader SAR displayed favorable brain penetration (Kps > 1, Kp,uus > 0.6) in our high-throughput rat plasma–brain level (PBL) cassette paradigm.28

Figure 3.

Figure 3

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Substituents explored in analogues 9, 16, 17, 18, and 19, which were inactive as mGlu7 PAMs.

Table 1. Structures and Activities of Analogues 9a.

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a

Calcium mobilization assays with rat mGlu7/Gqi5-HEK cells performed in the presence of an EC20 fixed concentration of L-AP4; values represent means from three (n = 3) independent experiments performed in triplicate.

b

Total and calculated unbound brain–plasma partition coefficients determined at 0.25 h postadministration of an IV cassette dose (0.20–0.25 mg/kg) to male, SD rats (n = 1), in conjunction with in vitro rat plasma protein and brain homogenate binding assay data. ND = not determined.

As discussed previously, HTS hit 5 exhibited improved selectivity for mGlu7 over previous compounds VU0155094 and VU0422288 (mGlu7 EC50 for 5 = 3.3 μM, pEC50 = 5.48 ± 0.14, 104 ± 5 L-AP4 Max, mGlu4 EC50 > 10 μM, mGlu8 EC50 > 10 μM) and displayed exceptional CNS penetration (rat plasma/brain Kp = 1.4, Kp,uu = 1.1). Moving the methoxy group to either the 2- or 3-position, as in 9a and 9b, respectively, led to inactive analogues, as did a wide-range of substituents across multiple domains of 5 (Figure 3). When steep SAR has presented in other GPCR allosteric modulator programs, application of the “fluorine walk” strategy31 has proven beneficial, and this is true for the present series. The addition of a single fluorine atom to either the 2- or 3-position of the 4-methoxyl phenyl moiety increased mGlu7 PAM activity (9c, mGlu7 EC50 = 1.5 μM, and 9d, mGlu7 EC50 = 1.7 μM), respectively. In the case of 9c, Kp (4.3) and Kp,uu (1.7) improved as well relative to 5. The addition of two fluorine atoms to the 4-methoxy phenyl moiety afforded even more favorable results. Here, the 2,6-difluoro congener 9e (mGlu7 EC50 = 0.60 μM, pEC50 = 6.22 ± 0.11, 107 ± 12 L-AP4 Max) and the 2,3-difluoro derivative 9f (mGlu7 EC50 = 0.65 μM, pEC50 = 6.19 ± 0.14, 112 ± 10 L-AP4 Max) provided submicromolar mGlu7 PAM EC50s and good CNS penetration (Kps of 2.2 (Kp,uu = 0.6) and 4.3 (Kp,uu = 2.3) for 9e and 9f, respectively). The 2-chloro-5-fluoro analogue 9h was the most potent mGlu7 PAM in the series (mGlu7 EC50 = 0.48 μM, pEC50 = 6.32 ± 0.06, but the efficacy was diminished (51 ± 7 L-AP4Max). Difluoromethyl ether congeners 9j and 9k were also active, but solubility concerns precluded further advancement.

The in vitro DMPK profiles (Table 2) and Kps/Kp,uus of 5 and analogues 9 were tightly conserved in terms of predicted hepatic clearance, protein binding, and CYP450 inhibition (note, the chemotype engenders 1A2 inhibition); thus, physiochemical properties of individual PAMs and mGlu7 PAM potency/efficacy assisted in prioritization. Attention then focused on further characterization of 9e and 9f as potential mGlu7 PAM in vivo tool compounds. Both PAMs 9e and 9f were predicted to be moderate to highly cleared in rat (CLhep = 64.2 and 65.5 mL/min/kg, respectively), and both displayed good free fraction in rat plasma (fu = 0.05 and 0.02; rat brain fu = 0.014 and 0.012) and clean CYP450 profiles (9e: >30 μM versus 3A4, 2D6, and 2C9, 8.7 μM at 1A2; 9f: >30 μM versus 3A4, 2D6, 24.6 μM at 2C9, and 3.1 μM at 1A2). Based on the improved rat Kp/Kp,uu, 9f was further advanced into a mouse PBL time-course study. Here, a 10 mg/kg IP dose of 9f was followed out to 6 h with nonserial sampling of both plasma and brain at each selected time point and displayed excellent CNS penetration (Kp @ 60 min of 2.1 and Kp @ 360 min of 1.1). Thus, for a first generation in vivo tool compound, 9f could be studied in both rat and mouse models.

Table 2. In Vitro DMPK Profiles of 5 and Analogues 9.

property 5 9c 9e 9f 9g
MW 321 339 357 357 357
cLogP 3.70 3.78 4.11 3.90 3.97
TPSA 43.2 37.2 37.2 37.2 37.2
in vitro PK parameters          
CLHEP (mL/min/kg), rat 59.4 62.1 64.2 65.5 63.0
CLHEP (mL/min/kg), human 18.8 18.5 14.2 16.6 15.0
rat fu,plasma 0.021 0.030 0.046 0.022 0.046
human fu,plasma 0.006 0.013 0.016 0.008 0.002
rat fu,brain 0.016 0.012 0.014 0.012 0.015
cytochrome P450 (IC50, μM)          
1A2 0.69 0.33 8.67 3.08 2.93
2C9 >30 27 >30 24.7 >30
2D6 >30 >30 >30 >30 >30
3A4 >30 >30 >30 >30 >30
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However, broader mGlu receptor selectivity, as well as general ancillary pharmacology, needed to be assessed prior to any in vivo work. Gratifyingly, 9f was inactive (EC50/IC50s > 10 μM) against mGlu1,2,3,4,5,6, but mGlu8 activity was present (mGlu8 EC50 = 2.6 μM, pEC50 = 5.58 ± 0.06, 101 ± 2 Glu Max, Table 3). Interestingly, 9f was inactive at the other Group III mGlus (mGlu4 and mGlu6, see Supporting Information).30 These data prompted us to examine mGlu selectivity for other analogues in this series, and in general, as PAM potency at mGlu7 increased, mGlu8 PAM activity also increased (Table 3); however, PAM activity at mGlu4/6 remained weak to inactive.30 PAM 9f represents a missing link in the Group III receptor PAM toolbox and serves as a nice complement to the mGlu4/8 PAM, 1. In addition, broader ancillary pharmacology was assessed in a Eurofins Lead profiling panel30 of 68 GPCRs, ion channels, and transporters, and a single activity assessment at NK1 (Ki = 650 nM, functional antagonist IC50 of 3.4 μM) proved significant (all others <50% inhibition of radioligand binding at 10 μM).31

Table 3. Comparison of Potency and % Maximal Agonist Response Across the Three Widely Expressed CNS Group III mGlu Receptors for 5, 9f, and Related Analogues.

entry mGlu4 EC50 (μM) [% agonist max ± SEM] mGlu4 pEC50 (±SEM) mGlu7 EC50 (μM) [% agonist max ± SEM] mGlu7 pEC50 (±SEM) mGlu8 EC50 (μM) [% agonist max ± SEM] mGlu8 pEC50 (±SEM)
5 >10 [48 ± 3] <5 3.3 [104 ± 5] 5.48 ± 0.14 >10 [86 ± 5] <5
9c >30 <4.5 1.5 [78 ± 2] 5.82 ± 0.06 2.0 [70 ± 6] 5.69 ± 0.13
9e >10 [69 ± 3] <5 0.60 [107 ± 12] 6.22 ± 0.11 2.9 [101 ± 1] 5.54 ± 0.18
9f >10 [45 ± 3] <5 0.65 [112 ± 10] 6.19 ± 0.14 2.6 [101 ± 2] 5.58 ± 0.06
9h >30 <4.5 0.48 [51 ± 7] 6.32 ± 0.06 0.49 [41 ± 10] 6.31 ± 0.06
9m 2.1 [53 ± 6] 5.67 ± 0.07 0.74 [102 ± 4] 6.13 ± 0.08 0.89 [85 ± 6] 6.05 ± 0.09
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With the first mGlu7-preferring, and highly CNS penetrant, PAM in hand, we assessed the activity of 9f in a standard rat preclinical model predictive of antipsychotic activity, amphetamine-induced hyperlocomotion (AHL),32 as human genetic association studies have identified GRM7 polymorphisms linked to schizophrenia.13,19 In this study, 9f was dosed at 30 mg/kg IP in 10% Tween 80/H2O (0.75 mg/kg. s.c. amphetamine), and there was no efficacy observed in this assay (data not shown).30 Terminal (t = 2 h) plasma and brain samples were taken, and 9f displayed a terminal Kp of 2.43 with total brain levels ∼9× above the mGlu7 PAM in vitro EC50. These data represent the first evaluation of an mGlu7/8 PAM in rat AHL, but the lack of efficacy here does not rule out potential efficacy with NMDA antagonist challenges or in other antipsychotic models (prepulse inhibition, conditioned avoidance responding, etc., or other genetic models (all of which are under pursuit)). As cognition deficits are another major, and unmet, symptom cluster in schizophrenia, we next evaluated 9f in a standard mouse contextual fear conditioning (CFC) model at 50 mg/kg IP.30 Here, 9f showed modest but significant pro-cognitive effects on associative learning in wild-type mice (Figure 4) and the first example of efficacy of an mGlu7/8 PAM in this model. We would note that the compound did induce some level of sedation, which was still present when the compound was evaluated in mGlu7 knockout mice. As sedation during training would be predicted to diminish the capacity for associative learning, it is likely that the full efficacy of PAM 9f in this cognitive assay was masked by off-target effects (such as NK1). Such results suggest that the utility of this tool may be limited in certain in vivo assays. Moreover, these exciting data warrant further optimization of this and other HTS hits to develop a highly selective mGlu7 PAM for further in vivo target validation studies.

Figure 4.

Figure 4

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VU6005649, 9f, administration has pro-cognitive effects on associative learning in wild type mice. (A) Contextual fear conditioning. Vehicle (10% Tween 80, n = 11) or 9f (VU6005649, 50 mg/kg, n = 11) was administered (i.p.) to mice 15 min prior to training. On test day, VU6005649-treated mice froze significantly more than vehicle-treated mice (vehicle, 65.5 ± 3.3%, vs VU6005649, 76.8 ± 3.6%, p = 0.03) indicative of procognitive compound effects on associative learning. Two-tailed students t test. Values presented as mean ± SEM.

PAM 9f, an mGlu7/8 PAM, and the first reported mGlu7 preferring PAM, complements existing Group III mGlu receptor PAM tool compounds 1–4, and represents a major advance in the field. This novel series of pyrazolo[1,5-a]pyrimidines possess good free fraction and CNS penetration, lending utility as both in vitro and in vivo tool compounds alone or in combination studies with 1–4 and Grm7–/– mice. Additional behavioral pharmacology with 9f and optimization of additional hits from the HTS screen are underway and will be reported in due course.

Acknowledgments

The authors would like to thank the NIH/NIMH MH102548 (to C.M.N.) and MH113543 (to C.M.N. and C.W.L.) and the William K. Warren, Jr. and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.). We would like to thank the Vanderbilt High Throughput Screening Facility for their assistance with primary screening.

Glossary

ABBREVIATIONS

AHL

amphetamine-induced hyperlocomotion

mGlu

metabotropic glutamate receptor

PAM

positive allosteric modulator

NAM

negative allosteric modulator

HTS

high-throughput screen

CFC

contextual fear conditioning

PBL

plasma/brain level

RTT

Rett syndrome

CNS

central nervous system

mGlu7

metabotropic glutamate receptor subtype 7

ADHD

attention deficit hyperactivity disorder

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00317.

  • General methods for the synthesis and characterization of all compounds, methods for the in vitro and in vivo DMPK protocols, supplemental figures, and detailed explanation of the sedation studies (PDF)

Author Contributions

⊥ These three authors contributed equally. C.W.L., C.M.N., P.J.C., and R.G.G. drafted/corrected the manuscript. M.A., M.S., K.A.B., and D.W.E. performed the chemical synthesis. C.W.L., P.J.C., C.M.N., C.J.K., and A.L.R. oversaw the target selection and interpreted the biological data. M.L. and A.L.R. performed the in vitro molecular pharmacology studies. A.L.B. and S.C. performed the in vitro and in vivo DMPK studies. C.K.J., M.B., and R.G.G. performed the in vivo experiments. All authors have approved the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml7b00317_si_001.pdf (1.3MB, pdf)

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ml7b00317_si_001.pdf (1.3MB, pdf)

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