Discovery of novel central nervous system penetrant metabotropic

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Brief Article

Discovery of novel central nervous system penetrant metabotropic glutamate receptor subtype 2 (mGlu) Negative Allosteric Modulators (NAMs) based on functionalized pyrazolo[1,5-a]pyrimidine-5carboxamide and thieno[3,2-b]pyridine-5-carboxamide cores 2

Elizabeth S Childress, Joshua M. Wieting, Andrew S Felts, Megan M Breiner, Madeline F Long, Vincent B Luscombe, Alice L Rodriguez, Hyekyung P. Cho, Anna L. Blobaum, Colleen M Niswender, Kyle A Emmitte, P. Jeffrey Conn, and Craig W Lindsley J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01266 • Publication Date (Web): 23 Oct 2018 Downloaded from http://pubs.acs.org on October 24, 2018

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Journal of Medicinal Chemistry

Discovery of novel central nervous system penetrant metabotropic glutamate receptor subtype 2 (mGlu2) Negative Allosteric Modulators (NAMs) based on functionalized pyrazolo[1,5-

a]pyrimidine-5-carboxamide and thieno[3,2-b]pyridine-5carboxamide cores Elizabeth S. Childress,§,‡ Joshua M. Wieting, §,‡ Andrew S. Felts,§,‡ Megan M. Breiner, §,‡ Madeline F. Long, §,‡ Vincent B. Luscombe,§,‡ Alice L. Rodriguez,§,‡ Hyekyung P. Cho§,‡, Anna L. Blobaum, §,‡ Colleen M. Niswender, §,‡,# Kyle A. Emmitte,§,‡, ψ P. Jeffrey Conn, §,‡,# Craig W. Lindsley*§,‡,ψ §Vanderbilt

Center for Neuroscience Drug Discovery, ‡Department of Pharmacology, ψDepartment of Chemistry, Vanderbilt University, Nashville, Tennessee 37232 #Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, KEYWORDS. Negative allosteric modulator (NAM), metabotropic glutamate receptor 2 (mGlu2), CNS penetration, structure-activity-relationship (SAR)

Supporting Information Placeholder ABSTRACT: A scaffold hopping exercise from a monocyclic mGlu2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu2 NAMs based on either a functionalized pyrazolo[1,5-a]pyrimidine-5-carboxamide core or a thieno[3,2-b]pyridine-5-carboxamide core. These novel analogs possess enhanced rodent PK, while also maintaining good mGlu2 NAM potency, selectivity (versus mGlu3 and the remaining six mGlu receptors) and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.

INTRODUCTION The presynaptic Group II metabotropic glutamate receptors (mGlu2 and mGlu3) are broadly expressed in the CNS and represent important therapeutic targets for a number of CNS disorders (e.g., anxiety, depression, schizophrenia, pain, addiction, Alzheimer’s disease (AD), and Parkinson’s disease (PD)).1-14 Early proof-of-concept (POC) studies were performed with dual orthosteric mGlu2/3 antagonists, agonists or PAMs (positive allosteric modulators), and thus the physiological and therapeutic roles of the individual subtypes was unclear.9-13 More recently, highly selective mGlu2 PAMs and mGlu3 NAMs have emerged with properties suitable for in vivo POC studies.14-20 Lilly has developed a highly selective orthosteric mGlu3 agonist, but no mGlu3 PAMs have been reported in the literature to date.21 Progress has been made in the development of mGlu2 NAMs (Figure 1), and are represented by 1-4. First generation mGlu2 NAM ligands (e.g., 1-3) are characterized by either poor physiochemical properties (e.g., high lipophilicity, low fu and poor solubility), rapid disposition (very high plasma clearance (CLp) and short half-life (t1/2)) and/or very low CNS penetration (rat brain:plasma partition ratios, or Kps of ≤0.3).22-25 In an attempt to address these limitations, we adopted a reductionist optimization strategy to simplify the mGlu2

NAM pharamacophore, and identified 4, a potent (IC50 = 78 nM, cLogP = 1.90), selective (>30 M versus mGlu1,3-8) and highly CNS penetrant (Kp = 1.9) mGlu2 NAM.24 While this was an advancement, the very high plasma clearance

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N

O NH2

HO

NH2

O

CH3 R1

N

N

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Br

O a

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O

N N

N N

b

R1

N

O R1

R1

c

F R2

OCH3

F

1

2

mGlu2 IC50 = 146 nM mGlu3 IC50 > 30 M

mGlu2 IC50 = 207 nM mGlu3 IC50 > 30 M Kp = 0.30

N

N

9

O

O

10 O

O N

O e

N N

HO

N

O f

N N

R1

R3 O

R

N N R1

R1

O

O

O

8

N d

R2

R2

R2

7

N

NH2

O

N

F

N

R2

NH2

11

O

R2

R2 12

g

13, R = OMe 14, R = NH2

Reagents and Conditions: (a) KOt-Bu, THF, dimethyl oxalate; then HCl (aq), 42-85%; (b) 3-bromo-1H-pyrazol-5-amine, HCl (aq), EtOH, 78 °C, 87-100%; (c) 10 mol% Pd(dppf), potassium vinyltrifluoroborate, EtNi-Pr2, n-PrOH:dioxanes (3:1), 90 °C, 51-93%; (d) OsO4, NMO, THF:DCM:H2O; then NaIO4, 74-84%; (e) NaBH4, DCM:MeOH, 0 ºC, 58-97%; (f) PPh3, Dt-BAD, DCM, R3OH, 0 ºC to 23 ºC, 15-79%; (g) NH3, MeOH, 150 ºC, µwave, 10-98%. a

O11CH3

F 4 mGlu2 IC50 = 78 nM mGlu3 IC50 > 30 M Kp = 1.9

3 mGlu2 IC50 = 45 nM mGlu3 IC50 > 30 M Kp = 0.30

Figure 1. Structures, pharmacology and rat CNS exposure data for reported mGlu2 NAMs 1-4. To date, only 4 displayed robust mGlu2 NAM potency coupled with high rat CNS penetration.

of 4 precluded its use as in vivo tool compound (mouse CLp = 118 mL/min/kg); however, 4 and related analogs are currently under investigation as putative PET tracers to enable biomarker and translational efforts.22-25 Here, we disclose further efforts towards the development of mGlu2 NAM in vivo tool compounds for POC studies, and the discovery of two new series of mGlu2 NAMs based on either a functionalized pyrazolo[1,5-a]pyrimidine-5-carboxamide core or a thieno[3,2-b]pyridine-5-carboxamide core from scaffold hopping exercises. RESULTS AND DISCUSSION Our scaffold hopping strategy is depicted in Figure 2 and centered on cyclization at the benzylic site to incorporate a fused 5-membered heterocycle (with or without a heteroatom at the ring fusion site) to produce two distinct 5,6-heterobicyclic systems, a pyrazolo[1,5a]pyrimidine-5-carboxamide core 5 or a thieno[3,2-b]pyridine-5carboxamide core 6. We desired a route that would

allow significant diversity to sample replacements for the western NMe pyrazole moiety and -efficient entry to the more limited set of substituted aromatic moieties (Ar) that engender mGlu2 NAM potency/efficacy.22-25 We first explored the pyrazolo[1,5-a]pyrimidine-5-carboxamide core 5, and developed a seven step synthetic route to access key derivatives 14 (Scheme 1).26 Starting from commercially available and appropriately substituted acetophenones 7, deprotonation and trapping with dimethyl oxylate provided 8. Condensation of 8 with 3-bromo-1H-pyrazol-5-amine delivered the desired the 2-bromro pyrazolo[1,5-a]pyrimidine core 9 in 87-100% yield. A subsequent Suzuki cross-coupling installed the vinyl moiety affording 10, which smoothly converted to the corresponding aldehyde 11 in good yield. Sodium borohydride reduction gave primary alcohol 12, and a substrate for diversification. Here, we first employed Mitsunobu chemistry to install heteroaryl Table 1. Structures and rat mGlu2 activities of analogs 14a O

N O N

N

N

R NH2

R1

Ar 5

R

R2

O N

14

NH2

S

F 4

NH2

N N

R3 O

NH2

N N

scaffold hopping

O alternate substituents

alternate moieties

N

O

5-membered fused heterocycle

Ar

Entry

R1

14a

H

R2

R3

6

Figure 2. Scaffold hopping strategy from mGlu2 NAM 4 to arrive at novel pyrazolo[1,5-a]pyrimidine-5-carboxamide and thieno[3,2b]pyridine-5-carboxamide cores 5 and 6, respectively.

F

OCH3 N

Scheme 1. Synthesis of pyrazolo[1,5-a]pyrimidine-5-carboxamide analogs 14a

14c

H

F

>10000 (10000 ----(50-fold loss of mGlu2 NAM functional potency. Still, multiple potent mGlu2 NAMs resulted, with several (14b-g) below 1 M potency (with cLogP = 2.8-3.9), and 14d (mGlu2 IC50 = 102 nM, pIC50 = 6.99±0.09, 1.5±0.3 % Glu min, cLogP = 3.92) was comparable to 4. While these potent mGlu2 NAMs 14b-g showed excellent CNS penetration (rat Kps = 2.5 to 2.7 and Kp,uus = 0.4 to 0.6), and are only the second mGlu2 NAM chemotype to display high CNS penetration, their in vitro DMPK profiles were suboptimal. While 14b-g did possess favorable fraction unbound in plasma (rat and human fus 0.03 to 0.12), they were highly bound in brain homogenate (rat brain fus 0.003 to 0.009, leading to lower pronounced Kp,uus) and showed high predicted hepatic clearance in microsomes (rat CLhep >58 mL/min/kg, human CLhep >15 mL/min/kg).26 The one exception, however, was 14c (mGlu2 IC50 = 794 nM, pIC50 = 6.10±0.07, 2.4±0.4 % Glu min, cLogP = 3.77), which displayed moderate fraction unbound in rat and human plasma (rat and human fus of 0.03 and 0.017, respectively) low unbound fraction in rat brain (fu = 0.007) and, for the first time within an mGlu2 NAM chemotype, moderate predicted hepatic clearance in microsomes (rat CLhep = 32.3 mL/min/kg, human CLhep = 6.6 mL/min/kg). To determine if there was an in vitro:in vivo correlation (IVIVC), 14c was dosed in a standard rat IV PK cassette (0.2 mg/kg per compound), where it demonstrated low plasma clearance in rat (CLp = 10.0 mL/min/kg), a long half-life (t1/2 = 4.28 hr) and a modest volume of distribution at steady state (Vss = 3.31 L/kg). To confirm these exciting and unprecedented PK data for an mGlu2 NAM, we then performed a discrete rat IV PK experiment (1 mg/kg) and found comparable, favorable data (rat CLp = 16.4 mL/min/kg, t1/2 = 5.53 hr, Vss = 6.59 L/kg). Moreover, 14c was highly selective for mGlu2 (>30 M versus mGlu1,3-8). Despite the moderate functional potency, 14c was a watershed moment for the field as all

16 mGlu2 IC50s 3.2 to 10 M

15 mGlu2 IC50s >10 M

4.2±7.4

NH2

N N

R3 N R4

R2

F F3C

N

NH2

N N

O

Br

14g

O

O R3

Figure 3. Steep SAR. Analogs of 14 that encompassed either functionalized aryl ethers 15 or secondary and tertiary amino-methyl congeners 16 were either devoid of mGlu2 NAM activity, or lost significant activity relative to 14. mGlu2 NAMs before it were either poorly CNS penetrant (Kps 10 M), and analogs 16 were weak to inactive (IC50s 3.2 to 10 M). Thus, SAR proved quite steep, which led us to explore alternative linkers from the pyrazolo[1,5-a]pyrimidine core to the western pyridine heterocycle. Based on 1, we explored an aliphatic ethyl linker terminating in functionalized pyridines to determine if a more ‘floppy’ presentation of the heterocycle would result in more robust SAR with analogs 20. This synthesis proved straightforward (Scheme 2).26 Starting from bromo intermediate 9, a Sonogashira coupling with trimethylsilyl acetylene afforded 17, which was then deprotected to provide the terminal acetylene 18 in 37% overall yield. A second Sonogashira reaction with functionalized halopyridines gave heterobiaryl acetylenes 19. Reduction of the alkyne and conversion of the methyl ester to the primary carboxamide produced the desired products 20. Scheme 2. Synthesis of pyrazolo[1,5-a]pyrimidine-5-carboxamide analogs 20a O N Si

a

9

O N

O

b

N N R1

R1

R2

R2

17

18 O

O

R3

N

c N


O

N N R1

d,e

N

R3

NH2

N N N

R1

R2

R2 19

O

N N

20

Journal of Medicinal Chemistry Reagents and Conditions: (a) TMS-acetylene, CuI, TEA, PdCl2(Ph3P)2, 48%, DMF, 120 oC; (b) TBAF, THF, 0 oC, 77%; (c) functionalized 3- or 4-bromopyridine, CuI, Et3N, PdCl2(Ph3P)2, DMF, 150 oC, 40%; (d) H2, Pd/C, MeOH, 72-80%; (d) NH3, MeOH, 150 oC, µwave, 62-69%. a

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Like with analogs 15 and 16, SAR with congeners 20 was steep (Table 2) with few active analogs produced (5 total examples and the majority had IC50s > 10 M). Of the actives, both an unsubstituted 3-pyridyl 20a was a weak mGlu2 NAM (IC50 = 1,740 nM, cLogP = 2.82), as was an unsubstituted 4-pyridyl analog 20b (IC50 = 1,050 nM, cLogP = 2.35). This series produced a lone standout, 20c, the desoxy congener of 14c, which was ~9-fold more potent (mGlu2 IC50 = 87 nM, pIC50 = 7.06±0.06, 2.3±0.2 % Glu min, cLogP = 3.85) than 14c, and comparable in potency to 4.25 In our standard rat plasma:brain level (PBL) IV cassette (0.2 mg/kg per compound), 20c showed good CNS penetration (Kp = 1.0, Kp,uu = 0.41), acceptable fraction unbound in rat and human plasma (fus of 0.043 and 0.021, respectively, and similarly low unbound fraction in rat brain, fu = 0.006), but unacceptable predicted hepatic clearance in microsomes (rat CLhep = 66.7 mL/min/kg and human CLhep = 19.4 mL/min/kg). Attempts to mitigate the high clearance by deuteration of the ethyl chain had no impact. Steep SAR in the pyrazolo[1,5-a]pyrimidine forced us to move on to explore the thieno[3,2-b]pyridine-5carboxamide core 6 in hopes that more tractable SAR would result, while maintaining the favorable CNS penetration and rat PK profile of the pyrazolo[1,5-a]pyrimidine 14c. Table 2. Structures and rat mGlu2 activities of analogs 20a O N

R3

intermediate gave 26 in good yields, followed by TBAF deprotection of the TIPS ether, which delivered linchpin 27. Alcohol 27 could be bifurcated to deliver aryl and heteroaryl ethers 28, via a Mitsuobu reaction followed by hydrolysis of the nitrile to the primary carboxamide 29. Alternatively, 27 could be also converted into the corresponding bromide with NBS, and then displaced with secondary amines to afford aminomethyl congeners 30. Finally, hydrolysis of the nitrile to the primary carboxamide 31, generated putative mGlu2 NAMs. The SAR for analogs 29 is shown in Table 3 for representative examples. Once again, aryl ethers, such as 29a, regardless of substitution patterns, were devoid of mGlu2 NAM activity. The Nmethyl pyrazole 29b, the thieno[3,2-b]pyridine-5-carboxamide congener of 4, was ~20-fold less potent (IC50 = 1514 nM, cLogP = 3.65), and the preferred heteroarylether moiety found in 14c, a 3-CF34-pyridine, also lost considerable activity (~20- fold) in the thieno[3,2-b]pyridine-5-carboxamide series, example 29d (IC50 = 1740 nM, cLogP = 5.24). Thus, it was clear that the SAR was quickly shaping up to be divergent between the two 5,6-heterobicyclic series. Several submicromolar mGlu2 NAMs did result from substituted 3pyridyl derivatives (29f-h and 29j-k), but potency barely exceeded 700 nM (cLogP = 4.45 to 5.26). Moreover, all of these analogs showed high predicted hepatic clearance in microsomes (rat CLhep >60 mL/min/kg and human CLhep >17 mL/min/kg), but acceptable CNS penetration (Kps >2, Kp,uus 95% as determined by analytical LCMS (214 nm, 254 nm and ELSD) as well as 1H and 13C NMR and Hi-Res MS. The general chemistry, experimental information, and syntheses of all other compounds are supplied in the Supporting Information.

CONCLUSION

Corresponding Authors

In summary, we have reported on the discovery of two new 5,6heterobicyclic series of mGlu2 NAMs, based on either a pyrazolo[1,5a]pyrimidine-5-carboxamide core or a thieno[3,2-b]pyridine-5carboxamide core that provided advances in the field. First, both series were highly CNS penetrant, with good functional potency and selectivity versus the other seven mGlu receptor subtypes. Importantly, an analog within these series was the first mGlu2 NAM to show attractive rat in vivo PK (low clearance and moderate halflife). Interestingly, these new chemotypes did not always show an IVIVC, making reliance on in vitro DMPK assays potentially problematic. While the ideal in vivo mGlu2 NAM did not result from this scaffold-hopping and optimization campaign, advances in CNS penetration coupled with rat PK were realized. Further optimization efforts in other 5,6-heterobibcyclic systems are in progress and will be reported in due course.

EXPERIMENTAL SECTION

2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-7-(4fluorophenyl)thieno[3,2-b]pyridine-5-carboxamide (31e ). To a vial containing 2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-7-(4fluorophenyl)thieno[3,2-b]pyridine-5-carbonitrile (30e) (80.0 mg, 0.210 mmol, 1.0 equiv.) was added potassium trimethylsilanolate (56.5 mg, 0.440 mmol, 2.1 equiv.) and THF (2.1 mL). The reaction mixture was heated to 70 oC for 2 h at which time LCMS indicated full consumption of the starting material. The reaction was cooled to rt and then quenched with 0.200 mL 2 N HCl. The reaction mixture was concentrated and then purified by reverse phase HPLC to give 32.6 mg of an off-white solid (39%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.83 – 7.76 (m, 1H), 7.68 – 7.59 (m, 2H), 7.14 – 7.01 (m, 2H), 5.69 – 5.59 (m, 1H), 3.66 (d, J = 1.1 Hz, 2H), 3.60 – 3.47 (m, 2H), 2.63 (dt, J = 10.4, 1.7 Hz, 2H), 1.70 (dd, J = 11.4, 9.9 Hz, 2H), 0.97 (d, J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 167.36, 164.80 (d, J(C,F) = 250.1 Hz), 162.31(d, J(C,F) = 250.1 Hz), 156.04, 150.60, 147.97, 144.04, 135.21, 133.74 (d, J(C,F) = 3.3 Hz), 133.71 (d, J(C,F) = 3.3 Hz), 130.20 (d, J(C,F) = 8.4 Hz), 130.12 (d, J(C,F) = 8.4 Hz), 123.36, 116.48 (d, J(C,F) = 21.9 Hz), 116.29, 116.26 (d, J(C,F) = 21.9 Hz), 71.77, 59.49, 58.17, 19.19; HRMS (ESI): calculated for C21H22FN3O2S [M]: 399.1417; found: 399.1419; LCMS RT = 0.774, ES-MS [M+1]+ : 400.4.

ASSOCIATED CONTENT Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. Experimental procedures and spectroscopic data for selected compounds, detailed pharmacology and DMPK methods (PDF). SMILES strings (CSV)

*Phone: 615-322-8700. [email protected].

Fax:

615-343-3088.

E-mail:

Funding Sources This work was generously supported by the NIH and NIMH, GrantR01 MH 099269 (K.A.E.) and Grant R01 MH108498 (C.W.L). The authors would also like to thank the Warren Family and Foundation for establishing the William K. Warren, Jr. Chair in Medicine (C.W.L.).

ABBREVIATIONS USED mGlu2, metabotropic glutamate receptor subtype 2; CRC, concentration-response-curve; NAM, negative allosteric modulator; Kp, plasma/brain partitioning coefficient; Kp,uu, unbound brain partitioning coefficient; PBL, plasma:brain level; SAR, structureactivity-relationships; POC, proof-of-concept

REFERENCES


Page 7 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(1) Niswender, C. M.; Conn, P. J. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 2010, 50, 295−322. (2) Testa, C. M.; Friberg, I. K.; Weiss, S. W.; Standaert, D. G. Immunohistochemical localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the rat basal ganglia. J. Comp. Neurol. 1998, 390, 5−19. (3) Schoepp, D. D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 2001, 299, 12−20. (4) Ohishi, H.; Shigemoto, R.; Nakanishi, S.; Mizuno, N. Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 1993, 53, 1009−1018. (5) Ohishi, H.; Ogawa-Meguro, R.; Shigemoto, R.; Kaneko, T.; Nakanishi, S.; Mizuno, N. Immunohistochemical localization of metabotropic glutamate receptors, mGluR2 and mGluR3, in rat cerebellar cortex. Neuron 1994, 13, 55−66. (6) Ohishi, H.; Neki, A.; Mizuno, N. Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: an immunohistochemical study with a monoclonal antibody. Neurosci. Res. 1998, 30, 65−82. (7) Richards, G.; Messer, J.; Malherbe, P.; Pink, R.; Brockhaus, M.; Stadler, H.; Wichmann, J.; Schaffhauser, H.; Mutel, V. Distribution and abundance of metabotropic glutamate receptor subtype 2 in rat brain revealed by [3H]LY354740 binding in vitro and quantitative radioautography: Correlation with the sites of synthesis, expression, and agonist stimulation of [35S]GTPγs binding. J. Comp. Neurol. 2005, 487, 15−27. (8) Wright, R. A.; Johnson, B. G.; Zhang, C.; Salhoff, C.; Kingston, A. E.; Calligaro, D. O.; Monn, J. A.; Schoepp, D. D.; Marek, G. J. CNS distribution of metabotropic glutamate 2 and 3 receptors: transgenic mice and [3H]LY459477 autoradiography. Neuropharmacology 2013, 66, 89−98. (9) O’Brien, N. L.; et al. The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder. Psychiatr. Genet. 2014, 24, 277−278. (10) Kalinichev, M.; Campo, B.; Lambeng, N.; Célanire, S.; Schneider, M.; Bessif, A.; Royer-Urios, I.; Parron, D.; Legrand, C.; Mahious, N.; Girard, F.; Le Poul, E. An mGluR2/3 negative allosteric modulator improves recognition memory assessed by natural forgetting in the novel object recognition test in rats. In memory consolidation and reconsolidation: Molecular Mechanisms II; Proceedings of the 40th Annual Meeting of the Society for Neuroscience, San Diego, CA, Nov 13−17, 2010; Society for Neuroscience: Washington, DC, 2010; 406.9/MMM57. (11) Choi, C. H.; Schoenfeld, B. P.; Bell, A. J.; Hinchey, P.; Kollaros, M.; Gertner, M. J.; Woo, N. H.; Tranfaglia, M. R.; Bear, M. F.; Zu-kin, R. S.; McDonald, T. V.; Jongens, T. A.; McBride, S. M. Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile X syndrome by group II mGluR antagonist or lithium treatment. Brain Res. 2011, 1380, 106−119. (12) Gatti McArthur, S.; Saxe, M.; Wichmann, J.; Woltering, T. mGlu2/3 Antagonists for the treatment of autistic disorders. PCT Int. Pat. Appl. WO 2014/064028 A1, May 1, 2014. (13) Structure of Decoglurant Disclosed in Recommended International Nonproprietary Names (INN). In WHO Drug Information; World Health Organization: Geneva, Switzerland, 2013; Vol. 27, no. 3, p 150. (15) Lindsley, C. W.; Emmitte, K. A.; Hopkins, C. R.; Bridges, T. M.; Gregory, K. J.; Niswender, C. M.; Conn, P. J. Practical strategies and concepts in GPCR allosteric modulator discovery: Recent advances with metabotropic glutamate receptors. Chem. Rev. 2016, 116, 6707− 6741.

(16) Trabanco, A. A.; Cid, J. M. mGluR2 positive allosteric modulators: a patent review (2009-present). Expert Opin. Ther. Pat. 2013, 23, 629−647. (17) Sheffler, D. J.; Wenthur, C. J.; Bruner, J. A.; Carrington, S. J. S.; Vinson, P. N.; Gogi, K. K.; Blobaum, A. L.; Morrison, R. D.; Vamos, M.; Cosford, N. D. P.; Stauffer, S. R.; Daniels, J. S.; Niswender, C. M.; Conn, P. J.; Lindsley, C. W. Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM. Bioorg. Med. Chem. Lett. 2012, 22, 3921−3925. (18) Wenthur, C. J.; Morrison, R.; Felts, A. S.; Smith, K. A.; Engers, J. L.; Byers, F. W.; Daniels, J. S.; Emmitte, K. A.; Conn, P. J.; Lindsley, C. W. Discovery of (R)−(2-fluoro-4-((−4-methoxy phenyl)ethynyl)phenyl(3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM). J. Med. Chem. 2013, 56, 5208−5212. (19) Walker, A. G.; Wenthur, C. J.; Xiang, Z.; Rook, J. M.; Emmitte, K. A.; Niswender, C. M.; Lindsley, C. W.; Conn, P. J. Metabotropic glutamate receptor 3 activation is required for long-term de-pression in medial prefrontal cortex and fear extinction. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 1196−1201. (20) Engers, J. L.; Rodriguez, A. L.; Konkol, L. C.; Morrison, R. D.; Thompson, A. D.; Byers, F. W.; Blobaum, A. L.; Chang, S.; Loch, M. T.; Niswender, C. M.; Daniels, J. S.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.; Emmitte, K. A. Discovery of VU0650786: A selective and CNS penetrant negative allosteric modulator of metabotropic glutamate receptor subtype 3 with antidepressant and anxio lytic activity in rodents. J. Med. Chem. 2015, 58, 7485−7500. (21) Engers, J. L.; Bollinger, K. A.; Rodriguez, A. L.; Long, M. F.; Breiner, M. M.; Chang, S.; Bubser, M.; Jones, C. K.; Morrison, R. D.; Bridges, T. M.; Blobaum, A. L.; Niswender, C. M.; Conn, P. J.; Emmitte, K. A.; Lindsley, C. W.; Weiner, R. L.; Bollinger, S. R. Design and synthesis of N-aryl phenoxyethoxy pyridines as highly selective and CNS penetrant mGlu3 NAMs. ACS Med. Chem. Lett. 2017, 8, 925-930. (22) Monn, J.A.; Henry, S.S.; Masset, S.M.; Clawson, D.K.; Chen, Q.; Diseroad, B.A.; Bhanrdwaj, R.M.; Atwell, A.; Lu, F.; Wang, J.; Russell, M.; Heinz, B.A.; Cartr, J.H.; Getman, B.G.; Adraqni, K.; Broad, L.M.; Sanger, H.E.; Ursu, D.; Catlow, J.T.; Swanson, S.; Johnson, B.G.; Shaw, D.B.; McKinzie, D.L.; Hao J. Synthesis and pharmacological characterization of C4β-amide-substituted 2aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY2794193), a highly potent and selective mGlu3 receptor agonist. J. Med. Chem. 2018, 61, 2302-2328. (23) Felts, A. S.; Rodriguez, A. L.; Smith, K. A.; Engers, J. L.; Morrison, R. D.; Byers, F. W.; Blobaum, A. L.; Locuson, C. W.; Chang, S.; Venable, D. F.; Niswender, C. M.; Daniels, J. S.; Conn, P. J.; Lindsley, C. W.; Emmitte, K. A. Design of 4-Oxo-1-aryl-1,4dihydroquinoline-3carboxamides as selective negative allosteric modulators of metabotropic glutamate receptor subtype 2. J. Med. Chem. 2015, 58, 9027−9040. (24) Zhang, X.; Kumata, K.; Yamasaki, T.; Cheng, R.; Hatori, A.; Ma, L.; Zhang, Y.; Xie, L.; Wang, L.; Kang, H. J.; Sheffler, D. J.; Cosford, N. D. P.; Zhnag, M.-R.; Liang, S. H. Synthesis and preliminary studies of a novel negative allosteric modulator, 7-((2,5- dioxopyrrolidin1yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2carboxamide, for imaging of metabotropic glutamate receptor 2. ACS Chem. Neurosci. 2017, 8, 1937-1948. (25) Bollinger, K.A.; Felts, A.S.; Brassard, C.J.; Engers, J.L.; Rodriguez, A.L.; Weiner, R.L.; Cho, H.P.;Chang, S.; Bubser, M.; Jones, C.K.; Blobaum, A.L.; Niswender, C.M.; Conn, P.J.; Emmitte, K.A.; Lindsley, C.W. Design and synthesis of mGlu2 NAMs with


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improve potency and CNS penetration based on a truncated picolinamide core. ACS Med. Chem. Lett. 2017, 8, 919-924. (26) See Supporting Information for full details.

TABLE OF CONTENTS GRAPHIC

O

5-membered fused heterocycle

N O N

N

N

R NH2

scaffold hopping

O

potency Ar rat PK

O alternate substituents

alternate moieties

NH2

N N

F

N R

S

NH2

CNS penetration

Ar


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Discovery of novel central nervous system penetrant metabotropic

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