An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders

Article abstract of DOI:10.1016/j.bmcl.2019.126681

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC₅₀ = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

Full text of DOI:10.1016/j.bmcl.2019.126681

Journal Pre-proof
An anthrone-based Kv7.2/7.3 channel blocker with improved
properties for the investigation of psychiatric and
neurodegenerative disorders
Jacob D. Porter, Oscar L. Vivas-Rodriguez, C. David Weaver,
Eamonn J. Dickson, Abdulmohsen Alsafran, Elliot DiMilo, Leggy
A. Arnold, Chris Dockendorff
PII:
S0960-894X(19)30631-6
DOI:
https://doi.org/10.1016/j.bmcl.2019.126681
BMCL 126681
Reference:
To appear in:
Received date:
Accepted date:
25 July 2019
9 September 2019
Please cite this article as: J.D. Porter, O.L. Vivas-Rodriguez, C.D. Weaver, et al., An
anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation
of psychiatric and neurodegenerative disorders, (2019), https://doi.org/10.1016/
j.bmcl.2019.126681
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An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved
Properties for the Investigation of Psychiatric and Neuro-
degenerative Disorders
Jacob D. Porter,† Oscar L. Vivas-Rodriguez,‡ C. David Weaver,∇ Eamonn J. Dickson,‡ Abdulmohsen
Alsafran,† Elliot DiMilo,§ Leggy A. Arnold,§ and Chris Dockendorff*,†
†Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI, 53201-1881, USA
‡Department of Physiology & Membrane Biology, University of California, 1 Shields Avenue, Davis, CA, 95616, USA
∇Departments of Pharmacology and Chemistry, Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville, TN, 37232, USA
§Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, WI, 53211, USA
KEYWORDS: Kv7 blocker; voltage-gated potassium channel; schizophrenia; DMP 543; JDP-107
ABSTRACT: A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known
compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility,
and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed
via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107)
with a promising combination of potency (IC50 = 0.16 휇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp as-
say, and drug-like properties.
Figure 1. Previous and planned KCNQ channel blockers
New and more efficacious treatments for schizophrenia are greatly needed, and this need has not yet been diminished by enor-
mous investments in the clinical investigation of new drug targets.1-3 One approach to schizophrenia drug discovery involves the
repurposing of compounds that have at least demonstrated safety in clinical trials.4 With this in mind, our interest in the chemical
modification and redesign of bioactive natural and unnatural scaffolds led us to reexamine blockers of specific voltage-gated potas-
sium channels of the family Kv7 (KCNQ). These are expressed in the nervous system, and two subtypes, KCNQ2 and KCNQ3,
combine to form heteromeric channels that regulate the excitability of neurons via the so-called M-current.5 Previously, certain
compounds possessing a rigid carbo- or heterocyclic core with two pendant Lewis basic sites were demonstrated to enhance the
release of acetylcholine (ACh) in neuronal tissue and were under clinical investigation as cognitive enhancers for the treatment of
dementia.6-11 Linopirdine (1)6,12-14 was well-tolerated but ineffective as a cognitive enhancer in a phase 3 trial with Alzheimer’s
patients.15 Subsequent work led to the characterization of these compounds as blockers of Kv7 (KCNQ) potassium channels that
1

control neuronal M-currents.16-20 More recently, a patent by Ghasemzadeh reported that the KCNQ2/3 channel blockers XE991 (2)7
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and DMP 543 (3),10,11 a compound also previously in clinical trials, could reverse the effects of phencyclidine (PCP) in a mouse
model of schizophrenia, as measured by prepulse inhibition, social interaction time, and forced delayed alternation task.21 The pa-
tent also claimed that such compounds could be used to attenuate the negative symptoms of schizophrenia or treat drug addiction.
Very recently, Shi and Xie reported that XE991 acts as a neuroprotective agent in a mouse model of Parkinson’s disease.22 These
findings prompted us to reexamine the use of KCNQ2/3 channel blockers for the potential treatment of neurological disorders, and
to identify novel compounds with improved properties.
Beginning with patent applications first submitted in the 1980s,23 researchers at DuPont Pharmaceuticals disclosed examples
of scaffolds with α,α-bispyridylmethyl substituents as neuronal ACh releasers for potential use as cognitive enhancers (compounds
1 to 4, Figure 1). With dozens of analogs previously disclosed in patents and publications, the pharmacophore for this compound
class is now well established, with a rigid central scaffold flanked by two pendant hydrogen bond accepting moieties. Linopirdine
and XE991 suffer from a lack of metabolic stability due to pyridine N-oxidation, which can be ameliorated by fluorination at the 2-
position of the pyridine (DMP 543).10 Two more recent examples of KCNQ2 blockers are UCL207724,25 and ML252,26 at least one
of which suffers from low metabolic stability.26 Based on the lack of any significant safety/toxicity issues reported for linopirdine
in the clinic,15 and the potency and stability of DMP 543,10 we focused our efforts on identifying novel anthrone-based KCNQ2/3
blockers that may have improved properties. In particular, DMP 543 has several liabilities, including low aqueous solubility (6 μM)
and a lack of stability under acidic conditions.27,28 Herein are described our efforts at addressing these issues with novel analogs
(Figure 1, bottom).
The acidic instability of DMP 543 is likely due to a SNAr mechanism whereby the pyridine is reversibly protonated prior to
attack by water at the 2-position, followed by elimination of fluoride.28 We reasoned that replacement of the 2-fluoro pyridine sub-
stituents with 2-trifluoromethyl (5) or 3,5-difluoro (6) could provide compounds that maintained KCNQ2/3 channel blocking activi-
ty and stability to pyridine N-oxidation while greatly improving stability under acidic conditions. We also reasoned that improved
solubility may be feasible without compromising metabolic stability by using alternative heterocycles. A 4-pyrimidine analog of
XE991 was reported, but it was more than tenfold less potent (EC50 = 4.4 vs 0.4 μM), and possessed less than 1% of the efficacy of
XE991 in an assay measuring ACh release.7 Extensive SAR studies have indicated that heteroatoms at the termini of both side
chains are required for ACh release activity,6,7,14 and we hypothesized that the pyridazine analog 7 could act as a hydrogen-bond
acceptor and perhaps maintain potency and efficacy. We would expect it to have improved metabolic stability relative to XE991,
improved solubility and acid stability relative to DMP 543,29 and a decreased volume of distribution, as suggested by its calculated
logP (clogP) that is 3 units lower than DMP 543 (2.9 versus 5.9, Figure 1). The 2-methylpyridine 8 was prepared as a control com-
pound to compare in particular with the 2-trifluoromethyl analog 5. Calculated pKa values of 5 to 8 suggest that they could all po-
tentially undergo salt formation with HCl (not possible with DMP 543), which could lead to improved kinetic solubilities and thus
potentially improved oral bioavailabilities.
Scheme 1. Representative synthesis of symmetrical bis-alkylated anthrone
1) ClCO2Et
NEt3
THF, 30 min
OMs
F
OH
O
OH
MsCl
NEt3
F
F
F
F
F
2) NaBH4
THF, 45 min
63%
DCM, 1 h
82%
N
N
11
10
N
9
N
F
F
N
N
F
F
F
1) NaI
THF, 60 °C 1 h
F
2) anthrone (12)
NaH
THF, 60 °C 14 h
46%
13
O
6
O
not isolated under optimal
conditions
Analogs 5–8 were synthesized by the alkylation of the anthrone scaffold with mesylate electrophiles, as reported by Pesti for
the synthesis of DMP 543.30 To provide suitable controls, we also synthesized DMP 543 itself. A representative synthesis is given
in Scheme 1 for 6; synthetic details for the preparation of the other compounds is provided in the Experimental section. Pyridine
carboxylic acid 9 was converted to a mixed anhydride, then reduced with NaBH4 to yield alcohol 10, which was converted to the
benzylic mesylate 11. The alkylation of anthrone with 11 to yield the final compound 6 was investigated by varying the base, addi-
tive, and solvent (Table 1). Initial optimization attempts explored different counterions for the tert-butoxide base with lithium and
potassium tert-butoxide (entries 1–3) both giving similarly low yields even upon further heating. These reactions also showed the
formation of monalkylated anthrone 13 by LC-MS as a prominent byproduct. Addition of 18-crown-6 ether (entry 4) to KOt-Bu did
not improve the yield. Increasing amounts of NaI (entries 5 and 6) gave only a slight improvement in yield over entry 1. The use of
NaH as the base (entry 7) was shown to significantly improve the conversion and yield of the second alkylation, as measured by
remaining 13 after completion of the reaction.
Table 1. Optimization of Anthrone Alkylationa
2

N
F
N
F
F
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conditions
F
12
O
6
O
entry
base
additivee
solvent/temp. % yieldb,c
1
2
3
4
5
6
7
LiOt-Bu
KOt-Bu
LiOt-Bu
–
–
–
THF/60 °C
THF/60 °C
THF/90 °Cd
THF/60 °C
THF/60 °C
THF/60 °C
THF/60 °C
3b
7b
12c
3b
7c
21c
46b,c
KOt-Bu 18-crown-6 (2.4 eq)
LiOt-Bu
LiOt-Bu
NaH
NaI (1.5 eq.)
NaI (2.0 eq.)
–
aGeneral conditions: (0.055 mmol) and base (0.132 mmol) were mixed in THF (4.0 mL). The anthrone/base solution was added to a solu-
tion of the mesylate (0.110 mmol) and NaI (varying equivalents) in THF (4.0 mL), which had been heated at 50 °C for 3 h prior to addi-
tion. The reactions were then stirred at 60 °C for 12–16 h. bIsolated yield. cYield measured by 1H NMR using pentachloroethane as internal
standard. dReaction run in sealed tube in an oil bath heated to 90 °C.
Compounds 5–8 were tested for their ability to block currents at a concentration of 1.5 μM in tsA201 cells expressing
Kv7.2/7.3, using a manual patch clamp protocol. The inhibition values for these preliminary screens are summarized in Table 2,
along with XE 991 and DMP 543. Compounds 6 and 8 were the only novel compounds of the initial group that showed significant
inhibition of Kv7.2/7.3 channel currents. 6 (65% inhibition) showed superior efficacy to DMP 543 (31% inhibition), and was com-
parable to the best-in-class compound XE991 (81%), at a concentration of 1.5 μM. Representative current traces are given for
XE991, DMP 543 and 6 in Figure 2.
Figure 2. Electrophysiology traces of XE991 (A), DMP 543 (B), and 6 (C), in tsA201 cells expressing KCNQ2/3. XE991 (20 μM) was
added late in each run to determine maximal channel inhibition.
Prior to in vitro metabolic stability studies, we measured the ability of our compounds to inhibit cytochromes P450 (CYPs),
specifically the subtype 3A4 most associated with drug metabolism (Table 2). Using high concentrations (50 μM), all compounds
inhibited CYP 3A4 to a significant degree, which is not surprising given the presence of pendant heterocycles in each compound
capable of coordinating to heme iron centers. The bispyridazine 7 showed the lowest level of inhibition (28%), which is not unex-
pected given that it is a less basic heterocycle and a weaker metal ligand.
Scheme 2. Synthesis of pyridine-pyridazine JDP-107 (18)
3

F
JournaNl Pre-proof
1) NaI
OMs
F
THF, 60 °C 1 h
F
F
2) anthrone (12)
LiOt-Bu
THF, 60 °C, 12 h
63%
N
O
11
13
OH
N
OMs
N
NaBH4
MeOH
CO2Me
CO2H
H2SO4
MsCl
DMAP
1h
33%
MeOH
70 °C, 14 h
N
N
15
N
THF,
15 min
N
N
N
17
61%
16
14
N
F
F
1) NaI
THF, 60°C, 30 min
N
N
2) 13
LiOt-Bu
THF, 60 °C 30 min
64%
O
18
JDP-107
Table 2. K+ channel and CYP 3A4 inhibition dataa
compound
Kv7.2/7.3 Kv7.2 flux hERG flux CYP 3A4
inhib.e
patch clamp IC50 (휇M)c IC50 (휇M)d
inhib.b
(@50 μM)
(@1.5 μM)
XE991 (2)
81%
0.055
0.048
5.6
>32
NT
DMP 543 (3) 31%
32
82%
95%
97%
28%
92%
N.T.
6%
inactive
12
5
6
7
8
65%
12%
33%
0.20
10
inactive
inactive
>32
0.54
JDP-107 (18) 73%
0.16
b
c
aSee Experimental section for assay protocols. N.T. = not tested. Patch clamp assay using tsA201 cells expressing Kv7.2/7.3. With
d
e
HEK-293 cells stably expressing Kv7.2 channels. With HEK-293 cells stably expressing hERG channels. CYP 3A4 activities were de-
termined using the Vivid CYP450 screening kit (Life Technologies, Carlsberg, CA, USA) according to the manufacturer's instructions.
To attempt to avoid the liability of CYP inhibition that could introduce drug-drug interactions upon clinical use, we considered
the preparation of unsymmetrically alkylated anthrones. The pharmacophore for these channel blockers (ACh releasers) is well
established to possess two pendant hydrogen bond acceptors, but we wished to determine if Kv7.2/7.3 could be effectively blocked
by compounds possessing one stronger and one weaker hydrogen bond acceptor. Wilkerson reported that compounds in the oxin-
dole series (e.g., linopirdine) can be highly efficacious acetylcholine release enhancers with one of the 4-pyridinylmethyl substitu-
ents replaced with an aliphatic ester or nitrile.6 We reasoned that a compound containing one pyridazine could maintain efficacy
and resistance to metabolic N-oxide formation, while potentially attenuating CYP inhibition. Such a compound is also expected to
possess improved solubility and decreased volume of distribution relative to DMP 543, which is likely a desirable clinical profile if
brain penetrance can be maintained.10
The synthesis of the pyridine-pyridazine 18 (JDP-107) is outlined in Scheme 2. Pyridazine-4-carboxylic acid (14) was convert-
ed to the methyl ester 15, then reduced with NaBH4 to generate alcohol 16. Anthrone (12) was sequentially alkylated with mesylate
11, then the mesylate 17 generated in situ from 16, thus generating the desired analog 18.
Figure 3. Concentration-response for JDP-107 (18) in Kv7.2 thallium flux assay. Error bars indicate standard error of the mean (SEM) for
3 wells.
4

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Next, the compounds were tested in a thallium flux assay using HEK-293 cells stably expressing Kv7.2 or hERG channels
(Table 2). 31 Compounds with sub-micromolar potencies showed similar maximal inhibition of Kv7.2, including XE991. DMP 543
was the most potent compound tested, with IC50 = 0.048 μM, very similar to XE991 (0.055 μM). The bis-trifluoromethylpyridine
analog 5 was ~100-fold less potent in the Kv7.2 assay, and showed minimal inhibition in the patch clamp KCNQ2/3 assay. The bis-
pyridazine 7 also showed only moderate inhibition of Kv7.2 (IC50 = 10 μM). The bis-methylpyridine analog 8 showed better poten-
cy in the Kv7.2 assay (IC50 = 0.54 μM). Pleasingly, the bis-(3,5-difluoropyridine) 6 showed good inhibition of Kv7.2 (IC50 = 0.20
μM) to go with its promising electrophysiology results. Comparable inhibition was also measured with the mixed pyri-
dine/pyridazine analog JDP-107 (18) (Figure 3, IC50 = 0.18 μM), within approximately 3-fold the potency of DMP 543. This con-
firmed our hypothesis that effective inhibition may be obtained with one more basic and one less basic moiety which presumably
act as H-bond acceptors within the channel. 18 also showed only minimal inhibition of the hERG channel, with no inhibition ob-
served at 1 μM and an IC50 > 30 μM. 6 showed a significantly higher level of hERG inhibition, with IC50 = 12 μM. Importantly, it
was also the most efficacious of the new analogs in the Kv7.2/7.3 patch clamp assay, with a maximal inhibition of 73%, significant-
ly better than DMP 543 (31%).
The success of the inhibitors 6 and 18 prompted us profile their drug-like properties in comparison to DMP 543 (Table 3).
Both DMP 543 and 18 inhibit CYP 3A4 substantially at a concentration of 10 μM, which could make for possible drug-drug inter-
actions in human subjects. Both compounds also show decent liver microsomal stability, with DMP 543 showing the better stability
after a 1 h incubation (97% vs 84% remaining). To compare the acid stability of compounds, DMP 543, 6, and 18 were subjected to
strongly acidic conditions (CH3CN/0.2N aq. HCl). Compounds 6 and 18 showed no degradation, and DMP 543 showed some deg-
radation (83% remaining after 24 h), based on HPLC analysis.
Table 3. Comparison of XE991, DMP 543, 6, and JDP-107 (18)a
XE991
81%
DMP 543
31%
6
JDP-107
(18)
65%
73%
Kv7.2/7.3 patch
clamp inhib.
(@ 1.5 μM)b
c
Kv7.2 flux IC50
hERG flux IC50
0.055 μM 0.048 μM 0.20 μM 0.16 μM
d
>32 μM
32 μM
12 μM
>32 μM
CYP 3A4 inhib.
N.T.
79%
N.T.
90%
(@ 10 μM)e
N.T.
97%
N.T.
84%
metabolic stability
(human liver mi-
crosomes)f
acid stabilityg
ClogPh
calc. pKah
tPSAi
CNS MPO scorej 4.0
kinetic solubilityk N.T.
N.T.
4.86
5.77
41.79
83%
5.93
>99%
5.43
>99%
4.17
–0.16
41.79
3.6
1.47
2.91
41.79
3.4
54.15
4.0
22 μM
30 μM
27 μM
N.T.
cytotoxicity
132 μM; 114 μM; >150
77 μM 79 μM μM
(CC50, hepG2 and
HEK-293 cells)l
Off-target
activitiesm
N.T.
6 (α1A Ki 2 (PBR 5 (D3 Ki
= 1.1–3.1 Ki = 2.5 > 10
μM; ꢀ1
Ki = 3.9
μM)
μM; ꢀ1 μM; ꢀ1
Ki = 1.8 Ki > 10
μM)
μM)
b
c
aSee Experimental section for assay protocols. N.T. = not tested. Patch clamp assay using tsA201 cells expressing Kv7.2/7.3. With
d
e
HEK-293 cells stably expressing Kv7.2 channels. With HEK-293 cells stably expressing hERG channels. CYP 3A4 activities were de-
termined using the Vivid CYP450 screening kit (Life Technologies, Carlsberg, CA, USA) according to the manufacturer's instructions.
g
fWith human liver microsomes; percent remaining after 1 h. Percent remaining based on relative HPLC peak areas (254 nm) after heating
h
at 60 °C in 1:1 MeCN:0.2N aq. HCl for 24 h at a concentration of 0.3 mM. Calculated with ChemAxon MarvinSketch v.18.3. iCalculated
j
with ChemDraw Prime v.16.0. Central Nervous System Multiparameter Optimization desirability score, calculated according to the
k
l
spreadsheet published by Wager et al.32 Using 2.5% DMSO/water. Measured using CellTiter-Glo® assay. mDefined as the number of
targets (of 40, mostly GPCRs) which show >30% binding at a concentration of 10 µM. These studies were performed by the National In-
stitute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP).
5

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To estimate the potential for our compounds to be safe CNS-active compounds, we used Pfizer's CNS multiparameter optimi-
zation desirability tool (CNS MPO), a freely available spreadsheet.32 For each molecule, ClogP, ClogD, total polar surface area
(tPSA), molecular weight, number of hydrogen-bond donors, and calculated pKa were determined and input into the spreadsheet to
determine the CNS MPO scores. ClogP, ClogD, and pKa were calculated with ChemAxon MarvinSketch v.18.3, and tPSA was
calculated with ChemDraw Prime v.16.0. The clinical compound DMP 543 possesses a score of 3.6 out of a possible 6, with 6 be-
ing the score for compounds with the most desirable properties for CNS drug development. The attenuated lipophilicity of 18 gave
it an improved score of 4.0. However, there was not a substantial increase in kinetic aqueous solubility with the addition of a pyri-
dazine to the scaffold (22 μM for DMP 543 vs 28 μM for 18). Both DMP 543 and 18 showed low cytotoxicity with hepG2 cells
using the CellTiterGlo® assay, with 18 showing no measurable cytotoxicity.
Finally, DMP 543, 6, and 18 were submitted to the Psychoactive Drug Screening Program for off-target screening against a
panel of mostly GPCRs, using competitive radioligand binding assays.33 JDP-107 showed >30% inhibition of 5 of 40 targets (most-
ly GPCRs); Kis were measured to be >10 휇M for the D3 and 흈1 receptors. We conclude that at this stage, it has a clean receptor
off-target binding profile for in vivo CNS studies.
We have determined that the anthrone scaffold of Kv7 inhibitors can tolerate replacements of pendant pyridine moieties with
alternative heterocycles, and that such compounds could have an improved range of properties more suitable for in vivo and clinical
studies. Specifically, we identified the pyridazine-containing analog 18 (JDP-107) that possesses comparable potency to DMP 543
in a Kv7.2 assay, superior efficacy in the Kv7.2/7.3 patch clamp assay, superior acid stability, and attenuated lipophilicity, though
solubility and CYP inhibition continue to be liabilities of this compound class. We anticipate that these liabilities could be ad-
dressed in future compounds via alternative heterocycles and/or the judicious incorporation of pyridazine substituents.
ASSOCIATED CONTENT
Supplemental Material
Synthetic protocols, assay protocols, and select compound characterization data.
AUTHOR INFORMATION
Corresponding Author
* Email: christopher.dockendorff@mu.edu Tel: +1-414-288-1617
Author Contributions
Designed compounds: C.D. Synthesized and characterized compounds: J.D.P., A.A. Optimized reactions: J.D.P. Measured acid stabilities:
J.D.P. Performed electrophysiology: O.L.V.-R., E.J.D. Performed ion flux assays: C.D.W. Performed compound profiling studies: E.D.,
L.A.A. Wrote the manuscript: C.D., J.D.P. Edited the manuscript and wrote the Supporting Info: C.D., J.D.P., C.D.W., E.J.D., L.A.A.
Funding Sources
C.D. thanks Marquette University for startup funding. E.J.D. was supported by R01GM127513 and University of California funds.
Notes
A preliminary version of this manuscript was submitted to the preprint server ChemRxiv.34 C.D.W. is an owner of WaveFront Biosciences
and ION Biosciences, manufacturers of the Panoptic plate reader and thallium-sensitive dyes used for the thallium flux assays described in
this manuscript.
ACKNOWLEDGMENT
We thank Dr. M. Behnam Ghasemzadeh (Marquette University) for helpful discussions; Dr. Sheng Cai (Marquette University) for assis-
tance with LC-MS and NMR instruments, and ACD Labs (NMR processing software) and ChemAxon Inc. (NMR and physicochemical
property prediction software). Off-target binding data was generously provided by the National Institute of Mental Health's Psychoactive
Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD
at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA.
ABBREVIATIONS
ACh, acetylcholine; clogP, calculated logarithm of ([n-octanol]/[water]) partition coefficient; CNS, central nervous system; CYP, cyto-
chrome P450; DCM, dichloromethane; DMAP, 4-dimethylaminopyridine; hERG, human ether-à-go-go-related gene, a voltage-gated po-
tassium channel equivalent to Kv11.1; KCNQ, voltage-gated potassium channels now identified as the family Kv7; Kv, voltage-gated po-
tassium channel; LAH, lithium aluminum hydride; NIMH, National Institute of Mental Health; MPO, multi-parameter optimization; PCP,
phencyclidine; Ms, methanesulfonyl or mesyl; PCP, phencyclidine; PDSP, Psychoactive Drug Screening Program; pKa, negative loga-
rithm of the acidity equilibrium constant; SAR, structure-activity relationship. THF, tetrahydrofuran; tPSA, topological polar surface area.
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