BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder

Article abstract of DOI:10.1021/acsmedchemlett.8b00080

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We

Full text of DOI:10.1021/acsmedchemlett.8b00080

Letter
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
BMS-986163, a Negative Allosteric Modulator of GluN2B with
Potential Utility in Major Depressive Disorder
Lawrence R. Marcin,*,† Jayakumar Warrier,‡,◆ Srinivasan Thangathirupathy,‡,◆ Jianliang Shi,§
George N. Karageorge,†,⊥ Bradley C. Pearce,† Alicia Ng,† Hyunsoo Park,§ James Kempson,§ Jianqing Li,§
Huiping Zhang,§ Arvind Mathur,§ Aliphedi B. Reddy,‡ G. Nagaraju,‡ Gopikishan Tonukunuru,‡
Grandhi V. R. K. M. Gupta,‡ Manjunatha Kamble,‡ Raju Mannoori,‡ Srinivas Cheruku,‡ Srinivas Jogi,‡
Jyoti Gulia,‡ Tanmaya Bastia,‡ Charulatha Sanmathi,‡ Jayant Aher,‡ Rajareddy Kallem,‡
Bettadapura N. Srikumar,‡ Kumar Kuchibhotla Vijaya,‡ Pattipati S. Naidu,‡ Mahesh Paschapur,‡
Narasimharaju Kalidindi,‡ Reeba Vikramadithyan,‡ Manjunath Ramarao,‡ Rex Denton,§
Thaddeus Molski,† Eric Shields,† Murali Subramanian,‡ Xiaoliang Zhuo,† Michelle Nophsker,†
Jean Simmermacher,† Michael Sinz,‡ Charlie Albright,†,∥ Linda J. Bristow,†,# Imadul Islam,‡,○
Joanne J. Bronson,† Richard E. Olson,† Dalton King,† Lorin A. Thompson,†,∇ and John E. Macor†,⊥
†Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
‡Biocon Bristol-Myers Squibb Research Center, Bangalore, India
§Bristol-Myers Squibb Research and Development, 3551 Lawrenceville Road, Princeton, New Jersey 08648, United States
S
* Supporting Information
ABSTRACT: There is a significant unmet medical need for more efficacious and
rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-
methyl-D-aspartate receptor subtype GluN2B have demonstrated encouraging
therapeutic potential. We report herein the discovery and preclinical profile of a
water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule
BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric
site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to
parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have
exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant
off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has
demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in
major depressive disorder.
KEYWORDS: BMS-986163, BMS-986169, GluN2B, negative allosteric modulator, ketamine, depression, preclinical candidate
intravenous (i.v.) infusion of ketamine at a subanesthetic dose
ajor depressive disorder (MDD) is a debilitating
Mpsychiatric condition affecting more than 350 million can impart rapid, robust, and sustained antidepressant effects in
treatment resistant patients.6 While these findings have fueled
off-label clinical use, ( )-ketamine has not been reviewed or
approved by the FDA for use as an antidepressant. Ongoing
trials may provide additional support for expanded labeling, but
the dissociative side effects experienced after ketamine infusion,
along with its abuse potential, are significant hurdles.7
Importantly, a nonracemic form of ketamine, S-ketamine
(esketamine), has received breakthrough therapy designations
with the FDA for both MDD and TRD indications. Esketamine
has recently demonstrated robust and durable antidepressant
efficacy as adjunctive therapy for patients with TRD and is
currently being evaluated in six ongoing phase 3 trials.8
people worldwide.1 Treatment typically includes a combination
of psychotherapy and antidepressant medications. Most of the
commonly prescribed antidepressants modulate monoamine
neurotransmitters and can require several weeks of repeat
dosing to reach full therapeutic effect.2 Unfortunately, 20−30%
of MDD patients fail to achieve an adequate response to
multiple courses of drug therapy and may be diagnosed with
treatment-resistant depression (TRD).3 Options for managing
TRD can include switching medications, combination therapy,
and augmentation with atypical antipsychotics.4 Each option
can take months to adequately explore and may not prove
effective. Consequently, there is clear and present need for the
discovery of more efficacious and rapidly acting antidepressants.
Ketamine, a clinical anesthetic, has received a great deal of
attention as an investigational treatment for TRD.5 Over the
past two decades, seven clinical trials have demonstrated that
Received: February 15, 2018
Accepted: April 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.8b00080
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ACS Medicinal Chemistry Letters
Letter
While the anesthetic properties of ketamine are attributed to
noncompetitive N-methyl-D-aspartate (NMDA) receptor bind-
ing, the neuropharmacology of its antidepressant activity
remains under discussion.9 A substantial body of research
suggests the mechanism of action may involve (i) initial NMDA
receptor antagonism producing a glutamate surge, (ii)
activation of AMPA receptors, and (iii) enhanced synapto-
genesis in the prefrontal cortex (PFC), resulting from activation
of the mTOR pathway.10 Other preclinical research has
attributed the antidepressant activity of ketamine to early and
sustained activation of AMPA receptors by one of its
metabolites, (2R,6R)-hydroxynorketamine.11
BMS-986169 (5) and its water-soluble prodrug BMS-986163
(6).20
The ligand-based pharmacophore model for Ifenprodil-like
GluN2B NAMs consists of two nonpolar aromatic rings
connected by a linker that typically contains a basic nitrogen
and spans 9−11 Å.21 Guided by this model, we designed and
prepared a variety of novel GluN2B NAMs with heteroatom
containing linkers having nonplanar conformational restrictions
that might impart superior selectivity and retain drug-like
properties. Incorporation of two independent ring constraints
produced the piperidinyl pyrrolidinone lead BMT-108908 (7,
Table 1). This compound displayed potent rat GluN2B binding
A variety of NMDA receptor subtypes with distinct
pharmacology and unique expression profiles coexist in the
central nervous system.12 Consequently, the pursuit of subtype-
selective modulators having ketamine-like activity and reduced
liabilities has been an active area of research.5 With respect to
GluN2B-subtype receptors, significant evidence including gene
deletion experiments in rodents,13 reduced expression levels in
the PFC of MDD patients,14 and pharmacological inhibition in
rodent models of depression has made GluN2B a compelling
target for antidepressant therapy.15 Toward this end, many
GluN2B-selective negative allosteric modulators (NAMs),
including compounds 1−4, have been reported in the literature
(Figure 1).16 In a proof-of-concept study, Traxoprodil (1) as
Table 1. Data for BMT-108908
assay
result
1.4 0.5
rat forebrain GluN2B Ki (nM)
GluN2B oocyte EP IC50 (nM)
mouse occupancy study dose (mg/kg, i.v.)
ex vivo GluN2B occupancy (%)
total plasma conc. of 7 (nM)
4.2
0.3,
1
60,
95
70 5,
0.56
340 35
mFST MED (mg/kg, i.v.)
ex vivo GluN2B occupancy (%)
total plasma conc. of 7 (nM)
75
150 70
10, 11, 12
6.8
plasma free fraction:human, rat, mouse (%)
pKa (protonated amine), spectrophotometric
hERG PC IC50 (nM)
620
affinity (Ki = 1.4 nM) and robust inhibition of GluN2B
receptor function (IC50 = 4.2 nM) in oocytes. BMT-108908
also demonstrated dose-dependent ex vivo GluN2B receptor
occupancy (60 and 95%) in mouse brain after i.v. dosing (0.3
and 1 mg/kg, respectively). In the mouse forced swim test
(mFST), a model commonly used for the evaluation of
antidepressant efficacy, BMT-108908 produced a dose-depend-
ent decrease in immobility with a minimum effective dose
(MED) of 0.56 mg/kg (i.v.).22 At the conclusion of the mFST
MED experiment, the average plasma concentration of BMT-
108908 was 150 nM and brain GluN2B receptor occupancy
was 75%. Data from this study and others revealed that
GluN2B receptor occupancy levels in excess of 70% correlated
with significant immobility in the mFST. Despite efforts to
impart target selectivity through conformational restriction,
safety characterization of BMT-108908 revealed significant
inhibition of hERG channels (IC50 = 620 nM). Given a narrow
multiple of 34-fold for plasma free drug concentration at the
MED versus the hERG IC50, further development of BMT-
108908 was halted. Continued medicinal chemistry efforts
focused on ameliorating hERG inhibition by modification of
BMT-108908 and related molecules through rational design.
The classic hERG motif,23 which includes a basic nitrogen
flanked by aromatic or hydrophobic groups, overlaps
considerably with the GluN2B pharmacophore.21 Indeed,
achieving selectivity against hERG had been a clear objective
of many past efforts to develop Ifenprodil-like GluN2B
NAMs.15 To disrupt interactions of the basic nitrogen in the
piperidinyl pyrrolidinone scaffold with hERG residues, we
explored both steric and electronic modulation of the
Figure 1. Negative allosteric modulators of GluN2B 1−5 and water-
soluble phosphate prodrug BMS-986163 (6).
adjunctive therapy for TRD has demonstrated a 60% response
rate, with 78% of responders having maintained a response for
at least 1 week.17 Despite these encouraging results, the
development of Traxoprodil was eventually terminated due to
cardiovascular safety concerns.18 In a pilot trial for MDD,
CERC-301 (formally, MK-0657) showed antidepressant effects
as determined by the Hamilton Depression Rating Scale, but
statistical significance was not achieved using the Montgom-
ery−Aberg Depression Rating Scale.19 CERC-301 has fast-track
designation for MDD and is continuing in Phase II studies. In
this Letter, we disclose medicinal chemistry efforts that
culminated in the discovery of an optimized GluN2B NAM
B
DOI: 10.1021/acsmedchemlett.8b00080
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ACS Medicinal Chemistry Letters
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Table 2. Screening Data for Fluorinated Piperidinyl Pyrrolidinones 5 and 8−13
a
Single most active diastereomer of all four isomers tested; stereochemistry was undetermined.
piperidine ring. Ultimately, inductive effects of β-fluorine atom
substitution to reduce the basicity of the piperidine was most
effective in attenuating hERG activity. The exercise was
undertaken in context of the 4-methylbenzyl substituted
pyrrolidinone analog 8, which demonstrated GluN2B binding
(Ki = 1.4 nM), receptor occupancy (92% at 1 mg/kg, i.v.), and
hERG inhibition (IC50 = 400 nM) similar to BMT-108908
(Table 2). All new analogs were screened for GluN2B binding
affinity and ex vivo receptor occupancy in mice. The occupancy
data served as a higher throughput translational surrogate for
the mFST. The 3-monofluoro- and 3,3-difluoropiperidinyl
diastereomers 5 and 9−12 demonstrated strong GluN2B
binding affinity that was within 6-fold of the parent molecule 8.
Importantly, compounds 5, and 10−12 all exhibited weak
hERG inhibition (IC50’s > 7.8 μM) and high ex vivo brain
GluN2B occupancy (87−95%, 3 mg/kg, i.v.). Overall, BMS-
986169 (5) with (3S,4S) stereochemistry displayed the best
combination of potent target affinity (Ki = 4.0 nM), high
occupancy (95% at 3 mg/kg, i.v.), and weak hERG inhibition
(IC50 = 28 μM). Incorporation of the (3S,4S)-fluoropiperidine
motif into the prior lead BMT-108908 produced compound 13,
which had slightly inferior binding affinity and no advantages
compared to BMS-986169.
Table 3. Detailed Profile for BMS-986169 (5)
assay
result
GluN2B binding Ki (nM)
cyno cortex
4.2 0.8
6.3 1.5
24 nM
human cortex
GluN2B oocyte EP IC50 (nM)
GluN2A/2C/2D oocyte EP at 3 μM (% inhibition)
AMES result
−2.4, 8.6, 7
negative
metabolic stability T1/2: human, rat mouse, cyno, dog
(min)
25, 2.7, 3.5, 12, 6.0
plasma free fraction: human, rat, mouse, cyno, dog (%) 6, 9, 12, 11, 7
a
CYP 450 HLM inhibition IC50 (μM)
>18
1.1
Caco-2, efflux ratio
PSA (Å2)
44
pKa, spectrophotometric (protonated amine)
4.4
b
shake flask log D at pH 7.4
2.9
melting point (°C)
186
0.002
1
aqueous solubility at pH 7.4 (mg/mL)
mFST MED (mg/kg, i.v.)
GluN2B occupancy (%)
73
total plasma conc. of 5 (nM)
brain conc. 5 /plasma conc. 5
270 130
2.8
c
d
i.v. pharmacokinetics
species
In light of the encouraging results with BMS-986169, this
compound was subjected to rigorous preclinical character-
ization.20 In addition to potent rat brain GluN2B binding,
compound 5 maintained high affinity for GluN2B receptors in
brain preparations from monkey and human (Table 3).20 BMS-
986169 also demonstrated potent and selective functional
inhibition of GluN2B in comparison to other NMDA receptor
subtypes, including GluN2A, GluN2C, GluN2D.20 In vitro
screening of BMS-986169 against a broad panel of G-protein
coupled receptors (including adrenergic α1), ion channels,
nuclear hormone receptors, and enzymes revealed no other
significant activity.20 BMS-986169 was negative in an
exploratory AMES study. Serum protein binding of BMS-
parameter
t1/2 (h)
mouse
rat
0.9
monkey
dog
2.1
3.6
75
1.5
CL (mL/min/kg)
Vss (L/kg)
54
15
17
8.2
530
2.3
1.7
2.1
AUClast (nM·h)
1,300
2,700
2,500
a
Panel of CYP human liver microsomes: 3A4-BFC and BZR, 1A2,
2B6, 2C8, 2C9, 2C19, 2D6. Octanol/water partitioning at pH 7.4. 1
mg/kg, 5 min i.v. infusion, vehicle = 10% DMAC, 10% EtOH, 30%
HPBCD, 50% water. CD1 mice, Sprague−Dawley rat, male
Cynomolgus monkey, male Beagle dog.
b
c
d
C
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ACS Medicinal Chemistry Letters
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986169 was within a 2-fold multiple across species with average
free fractions between 6 and 12%. BMS-986169 did not exhibit
potent inhibition of cytochrome P450 enzymes in human liver
microsomes (multiple CYPs IC50 > 18 μM), nor did it
demonstrate time-dependent CYP inhibition. BMS-986169 was
not a substrate for the Caco2 efflux transporter. With respect to
physiochemical properties, BMS-986169 has a low polar surface
area of 44 Å2 and a LogD = 2.9, which are properties consistent
with good brain uptake. The pKa of 4.4 for the protonated
piperidine nitrogen was approximately 2 log units lower than
the piperidine of BMT-108908 (7, Table 1) and reflects the
inductive effects of fluorine substitution. The melting point of
crystalline BMS-986169 was 186 °C, and the aqueous solubility
at pH 7.4 was 2 μg/mL.
In the mFST, BMS-986169 demonstrated an MED of 1.0
mg/kg (i.v.) at 73% ex vivo GluN2B receptor occupancy and an
average terminal plasma concentration of 270 nM (Table 3).20
The brain-to-plasma ratio in mice was favorable at 2.8. In
context of plasma free drug concentration at the MED versus
hERG IC50, the multiple was 875-fold. In a follow-up
cardiovascular safety assessment, BMS-986169 did not produce
an increase in QTcB in anesthetized guinea pig after i.v.
administration at all doses tested (2, 5, and 10 mg/kg) and with
free drug plasma concentrations up to 19 μM. Consistent with
ketamine-like synaptic strengthening,24 BMS-986169 demon-
strated enhanced ex vivo hippocampal long-term potentiation
(LTP) that was sustained for 24 h after dosing in rat.20 In clear
differentiation from ketamine, BMS-986169 did not produce
dissociative effects in monkeys and only displayed marginal
effects on locomotor hyperactivity in mice.20
for a transient period defined by the dose and infusion rate in a
clinical setting.
While the aqueous solubility of BMS-986169 was sufficient
to support low-dose i.v. preclinical experiments, formulation
and dose escalation for toxicology studies and potential clinical
investigations was not feasible. To address the issue, we
explored solubilizing prodrug modifications of the phenol
group present in BMS-986169. It was paramount to this
strategy that the prodrug be rapidly converted to parent after
i.v. administration to recapitulate the exposure profile observed
upon i.v. dosing of BMS-986169. While several phenolic
prodrugs of BMS-986169 were prepared, the dihydrogen
phosphate BMS-986163 (6) exhibited optimal properties for
an intravenous agent. The prodrug 6 was a zwitterionic
monohydrate with a sharp melting point of 172 °C. Crystalline
material had aqueous solubility of 19.9 mg/mL at pH 7.4. The
prodrug 6 was physically and chemically stable in the solid state
at 50 °C for up to 4 weeks. Aqueous solutions of 6 were stable
for up to 90 days at 25 °C. The prodrug itself demonstrated no
relevant in vitro biological activity. Prodrug to parent
conversion was rapid in rat, monkey, dog, and human blood
at 37 °C. After i.v. administration of prodrug 6 (1.2 mg/kg) in
Cynomolgous monkey, prodrug concentrations in the plasma
were undetectable 10 min postdose, and the plasma AUCtotal
exposure of active parent 5 was approximately 63% of that
observed from direct administration of 5 (1.0 mg/kg, i.v.).26
The loss in exposure was not accounted for, but it may be
attributed to metabolism of the prodrug prior to phosphate
cleavage. Exposure data for the metabolites met-1 and met-2
was collected in the monkey PK study. The carboxylic acid
met-1 displayed a plasma AUCtotal that was 36% of parent 5 and
AUCtotal for the lactam met-2 was 130% of parent. While in
vivo conversion of prodrug to parent was not quantitative, the
high solubility of 6 and its rapid conversion to 5 supported
additional in vivo studies and dose escalating toxicology
experiments. Specific to on-target pharmacology, the prodrug
6 produced robust levels of ex vivo GluN2B receptor
occupancy in rat, in vivo functional inhibition of [3H]MK-
801 binding in rat, and dose-dependent activity in novelty-
suppressed feeding (NSF) in mice after i.v. dosing.20
The metabolic stability of BMS-986169 was poor in rodent
liver microsomes (T1/2 = 2.7−3.5 min) and marginally better in
microsomes from higher species (T1/2 = 6.0−25 min) (Table
3). Biotransformation studies in microsomes and hepatocytes
revealed rapid turnover of BMS-986169 to greater than 15
unique metabolites. Across species, the prominent metabolites
were the carboxylic acid met-1 and N−H lactam met-2 (Figure
2). These metabolites resulted from oxidation of the p-tolyl
The safety and tolerability of BMS-986163 (6) was evaluated
in two studies. In a 4-day rat experiment, where prodrug 6 was
dosed at 10, 30, and 100 mg/kg/day (i.v.), there were no
significant clinical-pathological and histopathological observa-
tions at any dose. An average total plasma exposure of parent 5
in excess of 48 μM·h was observed at day 4 for the 100 mg/kg/
day dose group. In a monkey single-dose toxicokinetic
tolerability study at 3.6, 12, and 36 mg/kg (i.v.), all doses
were well tolerated with no significant drug related effects. The
high dose group exhibited an average Cmax = 19 μM and total
plasma AUC24 = 88 μM·h for parent 5.
The chemical syntheses of BMS-986169 (5) and its
corresponding prodrug BMS-986163 (6) are outlined in
Scheme 1. Suzuki coupling of the commercial boronate ester
14 with 4-benzyloxybromobenzene, followed by hydrobora-
tion/oxidation of the resulting product 15 provided the racemic
trans-hydroxypiperidine ( )-16. The first eluting enantiomer
(S,S)-16, obtained from preparative chiral supercritical fluid
chromatography (SFC), was fully deprotected to afford the
phenolic piperidine (S,S)-17. The bromopyrrolidinone ( )-21,
obtained in two steps from benzylamine 18, was coupled with
(S,S)-17 to provide hydroxypiperidine 22 as a mixture of
diastereomers. Retentive deoxyfluorination of 22 and separa-
Figure 2. Two major metabolites of BMS-986169 (5).
methyl group and N-dealkylation of the lactam, respectively.
The structures of both metabolites were confirmed through
independent syntheses. The metabolites did not show in vitro
activity against GluN2A-D nor a broad panel of other
pharmacologically relevant targets.25
In terms of i.v. pharmacokinetics, BMS-986169 demonstrated
high clearance in rodents and moderate clearance in higher
species (Table 3). Volume of distribution was high in mouse
but moderate in rat, monkey, and dog. The drug plasma half-life
was short across all species. Total drug exposure (AUClast) was
at least 2-fold better in monkey and dog than rodents. In a rat
PK study at 5 mg/kg (p.o.), BMS-986169 displayed poor oral
bioavailability (F = 2.5%). The observed PK parameters of
BMS-986169 supported an intravenous route of administration
for which >70% GluN2B receptor occupancy would be targeted
D
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ACS Medicinal Chemistry Letters
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a
Scheme 1. Synthesis of GluN2B NAM BMS-986169 (5) and Prodrug BMS-986163 (6)
a
Reagents: (a) 1-(benzyloxy)-4-bromobenzene, [(PPh3)P]2PdCl2, Na2CO3, DME/H2O (82%); (b) BF3OEt2, NaBH4, NaOH, H2O2, THF/EtOH
(87%); (c) SFC: Lux Cellulose-2 (43%); (d) H2, Pd/C, MeOH (85%); (e) HCl dioxane/MeOH (87%); (f) 2,4-dibromobutanoyl chloride, TEA,
Et2O (95%); (g) NaH, THF (50%); (h) DIEA, DMF (74%); (i) Deoxofluor, CH2Cl2 (27%); (j) SFC: Chiralpak AD (48%); (k) pyridine, DMAP,
POCl3, then H2O (5%).
tion of the lactam diastereomers provided compound 23 and
BMS-986169 (5). The relative and absolute stereochemistry of
BMS-986169 was unambiguously established through single
crystal X-ray diffraction using anomalous scattering refine-
ment.27 Preparation of the prodrug BMS-986163 (6) was
accomplished through reaction with phosphorus oxychloride
and hydrolytic workup.28
AUTHOR INFORMATION
Corresponding Author
*Phone 203-677-6701. E-mail: lawrence.marcin@bms.com.
ORCID
Lawrence R. Marcin: 0000-0003-0375-6252
Jianqing Li: 0000-0002-8445-9796
■
Present Addresses
∥Editas Medicine, Inc., Cambridge, Massachusetts 02141,
United States.
In summary, rational design efforts afforded a novel class of
conformationally restricted, piperidinyl pyrrolidinone GluN2B
NAMs. Fluorine substitution of the piperidine core reduced
nitrogen basicity and ameliorated hERG inhibition of this
chemotype. The optimized lead BMS-986169 (5) demon-
strated single digit nanomolar affinity for GluN2B receptors,
selective functional inhibition of GluN2B receptors in cells,
high brain GluN2B receptor occupancy in rodents, and
significant in vivo activity in rodent behavioral models used
for the evaluation of antidepressant drugs. The poor aqueous
solubility of BMS-986169 was addressed through preparation of
the water-soluble phosphate prodrug BMS-986163 (6). The
prodrug was stable in solution but was rapidly converted to
parent after i.v. administration. The prodrug was safe and well
tolerated in rat and monkey toxicology studies. The phosphate
prodrug BMS-986163 (6) is an optimized agent for the delivery
of GluN2B receptor NAM BMS-986169 (5) and merits further
evaluation in MDD and TRD.
⊥Sanofi, Waltham, Massachusetts 02451, United States.
#Sunovion Pharmaceuticals, Marlborough, Massachusetts
01752, United States.
∇Fulcrum Therapeutics, Cambridge, Massachusetts 02139,
United States.
○King Abdullah International Med Research Center, KSAU-
HS, Ministry of National Guard-Health Affairs, Riyadh, Saudi
Arabia.
Author Contributions
◆Senior contributing author. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Mathiazhagan Annadurai and Poornima Sheety for
synthetic chemistry efforts.
■
REFERENCES
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00080.
Experimental details for synthetic procedures and
associated chemical data for compounds 5−23, pharma-
cological screening data, and biological methods (PDF)
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DOI: 10.1021/acsmedchemlett.8b00080
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX