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Brief Article Cite This: J. Med. Chem. 2019, 62, 378−384

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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-5-carboxamide 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,†,‡,§ P. Jeffrey Conn,†,‡,∥ and Craig W. Lindsley*,†,‡,§ †

Vanderbilt Center for Neuroscience Drug Discovery, ‡Department of Pharmacology, §Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States ∥ Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States, S Supporting Information *

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[3,2b]pyridine-5-carboxamide core. These novel analogues 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.

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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 positive allosteric modulators (PAMs), and thus the physiological and therapeutic roles of the individual subtypes were unclear.9−14 More recently, highly selective mGlu2 PAMs and mGlu3 NAMs have emerged with properties suitable for in vivo POC studies.15−21 Lilly has developed a highly selective orthosteric mGlu3 agonist, but no mGlu3 PAMs have been reported in the literature to date.22 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 © 2018 American Chemical Society

properties (e.g., high lipophilicity, low f u, 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 μM versus mGlu1,3−8), and highly CNS penetrant (Kp = 1.9) mGlu2 NAM.24 While this was an advancement, the very high plasma clearance of 4 precluded its use as an in vivo tool compound (mouse CLp = 118 mL/min/ kg); however, 4 and related analogues are currently under investigation as putative PET tracers to enable biomarker and Special Issue: Allosteric Modulators Received: August 10, 2018 Published: October 23, 2018 378

DOI: 10.1021/acs.jmedchem.8b01266 J. Med. Chem. 2019, 62, 378−384

Journal of Medicinal Chemistry

Brief Article

Scheme 1. Synthesis of Pyrazolo[1,5-a]pyrimidine-5carboxamide Analogues 14a

a

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)Cl2, 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 °C, 58−97%; (f) PPh3, Dt-BAD, DCM, R3OH, 0−23 °C, 15−79%; (g) NH3, MeOH, 150 °C, μwave, 10− 98%.

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.

translational efforts.22−25 Here, we disclose further efforts toward 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[3,2b]pyridine-5-carboxamide core from scaffold hopping exercises.

provided 8. Condensation of 8 with 3-bromo-1H-pyrazol-5amine delivered the desired 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, a substrate for diversification. Here, we first employed Mitsunobu chemistry to install heteroaryl and aryl ethers 13, followed by conversion of the methyl ester to the final pyrazolo[1,5-a]pyrimidine carboxamide analogues 14 in varying yields under microwave-assisted conditions. SAR for analogues 14 was steep (Table 1), with subtle variations in substituents on the southern aryl ring (e.g., comparing 14a to 14b), leading to >50-fold loss of mGlu2 NAM functional potency. Still, multiple potent mGlu2 NAMs resulted, with several (14b−g) below 1 μM 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 = 2.5−2.7 and Kp,uus = 0.4−0.6), 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 f us 0.03−0.12), they were highly bound in brain homogenate (rat brain f us 0.003−0.009, 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 f us of 0.03 and 0.017, respectively), low unbound fraction in rat brain (f u = 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),

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RESULTS AND DISCUSSION Our scaffold hopping strategy is depicted in Figure 2 and centered on cyclization at the benzylic site to incorporate a

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

fused 5-membered heterocycle (with or without a heteroatom at the ring fusion site) to produce two distinct 5,6heterobicyclic systems, a pyrazolo[1,5-a]pyrimidine-5-carboxamide core 5 or a thieno[3,2-b]pyridine-5-carboxamide core 6. We desired a route that would allow significant diversity to sample replacements for the western N-Me 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 379



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Table 1. Structures and Rat mGlu2 Activities of Analogues 14a

Figure 3. Steep SAR. Analogues 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.

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. On the basis of 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 analogues 20. This synthesis proved straightforward (Scheme 2).26 Scheme 2. Synthesis of Pyrazolo[1,5-a]pyrimidine-5carboxamide Analogues 20a

a

Calcium mobilization assay with rmGlu2/TREx/Gα15-HEK cells performed in the presence of an EC80 fixed concentration of glutamate, values represent means from three (n = 3) independent experiments in triplicate. bAmplitude of response in the presence of 30 μM test compound as a percentage of maximal response to glutamate; average of n = 3.

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 h), 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 h, Vss = 6.59 L/kg). Moreover, 14c was highly selective for mGlu2 (>30 μM versus mGlu1,3−8). Despite the moderate functional potency, 14c was a watershed moment for the field as all mGlu2 NAMs before it were either poorly CNS penetrant (Kps 10 μM), and analogues 16 were weak to inactive (IC50s 3.2−10 μM).

a

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

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. Like with analogues 15 and 16, SAR with congener 20 was steep (Table 2) with few active analogues produced (five total examples and the majority had IC50s > 10 μM). Of the actives, both an unsubstituted 3-pyridyl 20a was a weak mGlu2 NAM (IC50 = 1740 nM, cLogP = 2.82), as was an unsubstituted 4pyridyl analogue 20b (IC50 = 1050 nM, cLogP = 2.35). This series produced a lone standout, 20c, the des-oxy 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 380



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Scheme 3. Synthesis of Thieno[3,2-b]pyridine Analogues 29 and 31a

a


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 (f us of 0.043 and 0.021, respectively, and similarly low unbound fraction in rat brain, f u = 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. Entry into the thieno[3,2-b]pyridine-5-carboxamide core was accomplished via a nine-step synthetic route (Scheme 3), starting with commercially available 7-chlorothieno[3,2-b]pyridine 21.26 Deprotonation at the 2-position with n-BuLi and quenching with DMF (both at −78 °C) afforded the desired aldehyde 22 in 64% yield. Reduction to the alcohol 23 with NaBH4, followed by silyaltion with TIPS-Cl afforded the silyl ether 24. Next, standard Suzuki couplings with appropriately functionalized aryl boronic acids provided 25 in yields ranging from 52 to 81%. Installation of the cyano group in the 5-position via a two-step sequence through the pyridine N-oxide 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 analogues 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 N-methyl pyrazole 29b, the thieno[3,2-b]pyridine-5-carboxamide congener of 4, was ∼20-fold less

Reagents and conditions: (a) n-BuLi, THF, −78 °C, 20 min, then DMF, −78 °C, 2 h, 64%; (b) NaBH4, MeOH, 0 °C to rt, 1 h, 81%; (c) TIPS-Cl, imidazole, DMF, 1 h, 93%; (d) aryl boronic acid, Cs2CO3, Pd(dppf)Cl2, H2O, 1,4-dioxanes, microwave, 125 °C, 1 h, 52−81%; (e) MCPBA, DCM, 1 h; (f) dimethyl carbamoyl chloride, TMS-CN, THF, 17 h, 50−74%; (g) TBAF, THF, 1 h, 91−94%; (h) R5OH, PPh3, Dt-BAD, THF, 0 °C to rt, 1 h, 28−93%; (i) KOTMS, THF, 70 °C, 2 h, 8−60%; (j) NBS, PPh3, DCM, 20 min, then HNR3R4, 1 h, 28−93%. a

potent (IC50 = 1514 nM, cLogP = 3.65), and the preferred heteroarylether moiety found in 14c, a 3-CF3-4-pyridine, also lost considerable activity (∼20- fold) in the thieno[3,2b]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 3-pyridyl derivatives (29f−h and 29j−k), but potency barely exceeded 700 nM (cLogP = 4.45−5.26). Moreover, all of these analogues 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 < 0.4, the latter moderate predicted hepatic clearance in microsomes (rat CLhep < 45 mL/min/kg and human CLhep < 14 mL/min/kg), see Table 5. In vivo, 29n (IC50 = 316 nM, cLogP = 3.80) showed suprahepatic clearance in rat (CLp = 389 mL/min/kg) with a very short half-life (t1/2 = 14.3 min) and with a high volume (Vss = 6.49 L/kg), and thus no IVIVC. Replacement of the OCH3 moiety with an OCD3 (29p), in hopes to mitigate the high clearance, afforded no improvement. Once again, efforts resulted in another mGlu2 NAM chemotype with very high clearance, not suitable for the development of in vivo POC tool compounds. In one of the early series of mGlu2 NAMs, represented by 2,23 diverse amino methyl moieties were quite active; therefore, we evaluated the related series of analogues 31 (Table 4). As with the related pyrazolo[1,5-a]pyrimidine 381



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a


moderate predicted hepatic clearance in microsomes (rat CLhep = 42.1 mL/min/kg, human CLhep = 14.4 mL/min/kg). Moreover, 31e was highly selective for mGlu2 (>30 μM versus mGlu1,3−8). Because of poor IVIVCs across both 5,6heterobicyclic systems, we immediately evaluated 31e in an in vivo rat IV PK study. Here, 31e showed hepatic clearance (CLp = 75 mL/min/kg) with a reasonable half-life (t1/2 = 1.5 h) driven by a high volume of distribution at steady state (Vss = 7.42 mL/kg). To improve exposure in vivo, we performed intraperitoneal (IP) dosing to avoid first pass metabolism and, hopefully, achieve exposure at or above the mGlu2 in vitro IC50 to enable POC studies. At 10 mg/kp ip, 31e achieved total plasma concentrations of 1.07 μM (Cmax) and 5.81 μM (AUC) with high total brain exposure (6.09 μM (Cmax) and 32.9 μM (AUC)), for a Kp of 5.67. When corrected for unbound brain concentrations (based on rat brain homogenate binding data), brain levels dropped to 30.4 nM (Cmax) and 165 nM (AUC). Thus, if in vivo efficacy is driven by total brain levels, 31e is a suitable tool; however, if driven by free brain levels, higher doses (>30 mg/kg) will be required to achieve efficacious free brain levels (if 31e shows dose-linear exposure). However, to definitively dissect the physiological role and therapeutic potential of mGlu2 NAMs, a compound that can readily

a


analogues 16, the majority of analogues 31 were inactive or weak mGlu2 NAMs (cLogP = 3.32−4.60), with one exception, 31e (mGlu2 IC50 = 550 nM, pIC50 = 6.26 ± 0.01, 2.3 ± 0.1% Glu min, cLogP = 4.36), which contains the same amine subunit found in structurally unrelated NAM 2.23 As shown in Table 5, NAM 31e was also highly CNS penetrant (Kp = 5.62 and Kp,uu = 0.52) with modest fraction unbound (rat and human f us of 0.055 and 0.015, respectively) and low unbound fraction in rat brain (f u = 0.005). Importantly, 31e showed 382



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Table 5. In Vitro DMPK and PBL Data for Select mGlu2 NAMs Property

14c

20c

29g

29n

31e

MW cLogP TPSA In Vitro PK Parameters rat CLHEP (mL/min/kg) human CLHEP (mL/min/kg), rat f u plasma human f u plasma rat f u brain rat PBL (IV, 0.2 mg/kg) Kp Kp,uu

431 3.67 92.6

429 3.85 83.4

393 4.76 77.1

406 3.93 98.6

411 4.36 77.1

32.3 6.6 0.03 0.01 0.007

66.7 19.4 0.04 0.02 0.006

52.3 12.7 0.02 0.05 0.003

48.3 11.6 0.02 0.01 0.003

42.1 14.4 0.05 0.01 0.005

4.04 0.86

4.25 0.59

7.99 0.20

3.41 0.49

5.67 0.52

achieve free brain levels above the functional IC50 at reasonable doses is required.

ASSOCIATED CONTENT

S Supporting Information *

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01266. Experimental procedures and spectroscopic data for selected compounds, detailed pharmacology, and DMPK methods (PDF) SMILES strings (CSV)

CONCLUSION In summary, we have reported on the discovery of two new 5,6-heterobicyclic series of mGlu2 NAMs based on either a pyrazolo[1,5-a]pyrimidine-5-carboxamide core or a thieno[3,2b]pyridine-5-carboxamide 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 analogue within these series was the first mGlu2 NAM to show attractive rat in vivo PK (low clearance and moderate half-life). 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.

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AUTHOR INFORMATION

Corresponding Author

*Phone: 615-322-8700. Fax: 615-343-3088. E-mail: craig. [email protected]. ORCID

Kyle A. Emmitte: 0000-0002-6643-3947 Craig W. Lindsley: 0000-0003-0168-1445 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was generously supported by the NIH and NIMH, grant R01 MH 099269 (K.A.E.) and grant R01 MH108498 (C.W.L). We also thank the Warren Family and Foundation for establishing the William K. Warren, Jr. Chair in Medicine (C.W.L.).

EXPERIMENTAL SECTION

Chemistry: All compounds were purified to ≥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. 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 °C 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 of 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.

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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, structure−activity relationships; POC, proof-ofconcept

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REFERENCES

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