Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1

Article abstract of DOI:10.1016/j.bmcl.2017.10.062

This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE₂ production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED₅₀ of 14.3 mg/kg in guinea pig.

Full text of DOI:10.1016/j.bmcl.2017.10.062

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole
derivatives as potent and orally efficacious microsomal prostaglandin E
synthase-1 (mPGES-1) inhibitors: Part-1
Nagarajan Muthukaman a, Macchindra Tambe a, Sanjay Deshmukh a, Dnyandeo Pisal a, Shital Tondlekar a,
Mahamadhanif Shaikh a, Neelam Sarode a, Vidya G. Kattige b, Monali Pisat b, Pooja Sawant b,
Srinivasa Honnegowda b, Vikas Karande b, Abhay Kulkarni b, Dayanidhi Behera c, Satyawan B. Jadhav c,
Ramchandra R. Sangana c, Girish S. Gudi c, Neelima Khairatkar-Joshi b, Laxmikant A. Gharat a,
⇑
a Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India
b Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India
c Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic
benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 pro-
duction in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors
having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes.
Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic prop-
erties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavail-
ability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the
representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia
with an ED50 of 14.3 mg/kg in guinea pig.
Received 14 August 2017
Revised 18 October 2017
Accepted 25 October 2017
Available online xxxx
Keywords:
Benzofuran
Prostanoid
Inflammation
Scaffold hopping
Hyperalgesia
PGE2
Ó 2017 Elsevier Ltd. All rights reserved.
Osteoarthritis
Prostaglandin E2 (PGE2) is a lipid mediator, produced in abun-
dance by most mammalian tissues and regulates multiple biologi-
cal processes under pathophysiological conditions.1 In addition to
being a key mediator of pathological inflammation, PGE2 also plays
an important role in cellular physiological events such as neuronal
functions via prostanoid E receptors (EPRs), female reproduction,
vascular hypertension, kidney function and gastric mucosal protec-
tion. PGE2 has also been shown to support tumor growth by induc-
ing angiogenesis, modulating tumor-cell apoptosis, suppressing
immune surveillance and to induce colon carcinogenesis in the
presence of bile acid.2 Increased levels of PGE2 in the synovial fluid
of patients with rheumatoid arthritis (RA) and osteoarthritis (OA)
was observed from published studies.3 The role of prostaglandins
(PGs) in inflammatory pain is well established. Specifically PGE2
is one of the most endogenous substances known and mediates a
number of inflammatory processes including redness, swelling
and pain. Binding of PGs to prostanoid receptors (EP1, EP2, EP3
and EP4) sensitizes pain specific neurons to stimulate pain in cen-
tral nociceptive systems and mPGES-1 expression was strongly up-
regulated in the brain and spinal cord during inflammation.4a–d
Therefore, mPGES-1 enzyme which is functionally coupled to
COX-2 results in an increased formation of PGE2, which has
major role in nociception and analgesic activity.4e Taking into
consideration the multiple roles of PGE2, targeting the PGE2
synthesis pathway is of importance to several inflammation-
driven diseases such as arthritis, fever, cardiovascular
dysfunction, periodontitis, pain, inflammatory bowel and bone
disorders.5
The biosynthesis of PGE2 proceeds from arachidonic acid (AA),
which is metabolized into the unstable endoperoxide PGH2 by
COX-1 or COX-2. PGH2 is further isomerized into PGE2 by terminal
PGE synthases (PGES), such as membrane PGES (mPGES-1 and
mPGES-2) and cytosolic PGES (cPGES).6 mPGES-1 is a member of
the Membrane-Associated Proteins involved in Eicosanoid and
Glutathione metabolism (MAPEG) superfamily.6 Also, mPGES-1
⇑
Corresponding author.
E-mail address: Laxmikant.gharat@glenmarkpharma.com (L.A. Gharat).
https://doi.org/10.1016/j.bmcl.2017.10.062
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Muthukaman N., et al. Bioorg. Med. Chem. Lett. (2017), https://doi.org/10.1016/j.bmcl.2017.10.062

2
N. Muthukaman et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Fig. 1. Structure of known mPGES-1 inhibitors.
requires glutathione as an essential cofactor for its activity and is
predominantly up-regulated and functionally coupled to COX-2.7
mPGES-1 expression is very low in most normal tissues. However,
constitutive and copious expression is detected in a limited num-
ber of organs including the lungs, kidneys and reproductive organs.
mPGES-1 is an inducible isoform, which plays a predominant role
under inflammatory conditions8 and its expression can be specifi-
carboxamide (5, hIC50: 8 nM)20 and quinazolinone (6, hIC50: 5
nM)21 also demonstrated sufficient mPGES-1 potency. Further, Eli
Lilly (LY3023703)22 and our group (GRC27864)23 has moved
mPGES-1 inhibitors to human clinical development for inflamma-
tory diseases.
In a prior study inspired from benzimidazole-5-carboxamide 3,
we disclosed the structure-activity relationship (SAR) of
aminobenzimidazole-5-carboxamide 5 as a potent mPGES-1 inhi-
bitor with oral in vivo efficacy in a pain model of hyperalgesia.20
Also, no further updates were available to compound 3 other than
published patents.17,18 Consequently, as part of our on-going drug
discovery program, we designed novel scaffold from the known
structure 3 by applying ring closure scaffold hopping strategy24
and this resulted rigid tricyclic benzimidazole core 7 and 8 which
was expected to retain similar mPGES-1 potency as exemplified
in Fig. 2.25 In this manuscript, we describe the synthetic chemistry
approach towards optimization of tricyclic 1H-benzofuro[4,5-d]
imidazole series 7 and 8 and its pharmacological profile.
cally induced by lipopolysaccharide (LPS), IL-1b and TNF-a in var-
ious cell types with or without induction of COX-2.9 Genetic
deletion studies have highlighted the importance of COX and
mPGES-1 in different mouse models of arthritis, reducing inci-
dence, severity and pain in knock-out mice under the relevant
experimental settings.10a,10b Because of its key role in PGE2
synthesis, mPGES-1 has attracted attention as a potential drug
target in the areas of inflammatory diseases.10
The primary limitations related to the use of commercially
available anti-inflammatory drugs (NSAIDs and Coxibs), which
decreases PGE2 levels by blocking COX enzymes, are having cardio-
vascular, gastrointestinal, and renal side effects.9b Therefore, there
is a strong need to develop safer alternatives for long-term
therapies use. In this aspect, mPGES-1 inhibitors could epitomize
The syntheses of furan-fused benzo[d]imidazole derivative 7
and dihydrofuran-fused benzo[d]imidazole derivative
8 are
depicted in Schemes 1 and 2.25 Commercially available 4-aminos-
alicylic acid 9 was acetylated with Ac2O, followed by nitration in
TFA using sodium nitrite (NaNO2) to afford nitrated compound
10.26 Esterification of compound 10 with conc. H2SO4 in methanol
at 90 °C gave N-deacetylated ester product 11 in 75% yield.26 Next,
the furan-fused intermediate 13 was obtained by alkylation of
alcohol 11 using propargyl bromide, followed by intramolecular
cyclization27 in N,N-dimethylaniline at high-temperature. Iron-
aq. HCl mediated nitro-reduction of compound 13 provided dia-
mine 14 in 55% yield. Then, the aryl isocyanate 15 prepared from
the corresponding anilines,28 reacted with 1,2-diamino compound
14 in the presence of N,N0-diisopropylcarbodiimide (DIC) furnished
tricyclic compound29 16 and further ester hydrolysis provided key
acid intermediate 17 for further analoging. The carboxylic acid 17
was coupled with both aliphatic and aromatic amines using either
acid chloride or TBTU coupling method to provide amide deriva-
tives 7a–l (Table 1) in moderate yield as shown in Scheme 1.
The furan-fused tricyclic benzo[d]imidazole analogs 7a–l were
screened for mPGES-1 potency in order to understand scaffold via-
bility. The inhibitory activity of aliphatic amide derivatives, such as
isopentyl, cyclohexylmethyl and cyclohexyl derived amides 7a–e
gave reasonable mPGES-1 potency with IC50 values in the range
of 11–82 nM (Table 1).30 Despite having adequate potency, 7a–e
revealed poor metabolic stability in human and guinea pig liver
a
valuable pharmacological approach without affecting the
formation of PGH2 pharmacologically produced by the COXs. The
other terminal enzyme mPGES-2 is not essential for PGE2
synthesis in in vivo as reported in mPGES2-deficient mouse
study.11
Numerous mPGES-1 inhibitor chemotypes have been identified
in the course of research towards this target12 and few are exem-
plified in Fig. 1. Among these, MF-63 (1) was the first mPGES-1
inhibitor to be identified as an in vivo active (oral) with superior
enzyme and moderate cellular potency (hIC50: 1 nM and A549 cell
IC50: 420 nM).3a,11b,13 MF-63 also exhibited similar potency in
guinea pig (IC50: 0.9 nM) and was not active in both mouse and
rat enzyme due to significant differences in the protein sequence
of the substrate binding site.14 Furthermore, MF-63 selectively
suppressed the biosynthesis of PGE2 without affecting other pros-
taglandins in the in vivo models (LPS-induced pyresis, hyperalgesia,
and iodoacetate-induced OA pain model)13a tested in guinea pig.
Next, PF-4693627 (2) provided acceptable enzyme and human
whole blood potency (IC50 values 3 nM and 109 nM)15 and pro-
longed mPGES-1 inhibition using PF-4693627 (2) did not affect
the renal function as disclosed recently.16 Other inhibitors such
as aminobenzimidazole-5-carboxamide (3, hIC50: 3 nM),17,18 pyri-
dine-3-carboxamide (4, hIC50: 0.9 nM),19 aminobenzimidazole-5-
Please cite this article in press as: Muthukaman N., et al. Bioorg. Med. Chem. Lett. (2017), https://doi.org/10.1016/j.bmcl.2017.10.062

N. Muthukaman et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
Fig. 2. Structure 7 and 8: R1 = alkyl, cycloalkyl, aryl and heteroaryl; X = Cl, F; Y = C or N.
Scheme 1. Reagents and conditions: (a) Ac2O, EtOH, reflux; (b) NaNO2, TFA, ꢀ5–0 °C, 2 h, 70% for two steps; (c) MeOH, conc.H2SO4, reflux; 80%; (d) propargyl bromide, K2CO3,
DMF, 80 °C, 8 h, 55%; (e) N,N-dimethylaniline, CsF, 230 °C, 24 h, 35%; (f) Fe, aq.HCl, 0 °C to rt, 1 h, 55%; (g) thiophosgene, DIPEA, DCM, 0 °C to rt, 4–6 h; 60–80%; (h) N,N0-
diisopropylcarbodiimide, Ar-NCS, CH3CN, rt, 24 h, 60–75%; (i) 10% NaOH, MeOH, 60 °C, 8–10 h, 60–70%; (j) SOCl2, DCM, reflux, 2 h, then DIPEA, DCM, aryl amine/alkyl amine,
4–6 h, 30–55%; or TBTU, HOBT, DIPEA, 2 h, then aryl amine/alkyl amine, rt, 8–10 h, 40–60%.
Scheme 2. Reagents and conditions: (a) methallyl chloride, K2CO3, DMF, 80 °C, 9 h, 55%; (b) AlCl3, DCM, ꢀ70 °C to rt, 18 h, 73%; (c) Fe, aq.HCl, 0 °C to rt, 2 h, 45%; (d)
thiophosgene, DIPEA, DCM, 0 °C to rt, 4–6 h; 60–80%; (e) N,N0-diisopropylcarbodiimide, Ar-NCS, CH3CN, rt, 24 h, 40–60%; (f) 10% NaOH, MeOH, 60 °C, 8–10 h, 70–75%; (g)
SOCl2, DCM, reflux, 2 h, then DIPEA, DCM, aryl amine/alkyl amine, 4–6 h, 30–55%; or TBTU, HOBT, DIPEA, 2 h, then aryl amine/alkyl amine, rt, 10–14 h, 30–60%.
microsomes (<50% remaining after 60 min incubation).30 Next, the
introduction of 4-fluorobenzyl amine derived amides 7g and 7f
(IC50s: 58 nM and 157 nM) demonstrated 4–12-fold reduced
enzyme potency in comparison to 7b–d. In order to improve meta-
bolic stability and retain superior potency, substituted anilines
were introduced. Compounds bearing para- and ortho-fluo-
rophenyl, para- and meta-trifluoromethylphenyl derived amides
7h–l demonstrated single digit mPGES-1 enzyme potency with
Please cite this article in press as: Muthukaman N., et al. Bioorg. Med. Chem. Lett. (2017), https://doi.org/10.1016/j.bmcl.2017.10.062

4
N. Muthukaman et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Table 1
diisopropylcarbodiimide to afford tricyclic dihydrobenzofuro
aminoimidazole derivative 21 in 40–60% yield (two steps).29 The
ester derivative 21 was hydrolyzed to carboxylic acid derivative
22 in the presence of 10% NaOH solution, followed by coupling
with various alkyl and aryl amines (Table 2) using either acid chlo-
ride method or TBTU mediated coupling to afford amide deriva-
tives 8a–w in 30–60% yield.
SAR of furan-fused benzo[d]imidazole.
The biological activity of dihydrofuran-fused benzimidazole
analogs 8a–w were evaluated for mPGES-1 potency and metabolic
stability. Since, alicyclic amides 7a–e were metabolically less
stable (Table 1), we introduced few more alicyclic amides, includ-
ing fluorinated in the dihydrofuran series 8 in order to afford
metabolically stable analogs with reduced aromatic ring counts.32
Among the synthesized alicyclic amide derivatives 8a–e, potent
analogs 8a–b and 8e were metabolically less stable (<50%) in both
human and guinea pig liver microsomes (HLM and GPLM).30 But,
cyclopropylmethyl derived amide 8c exhibited good metabolic sta-
bility (>70%) even though it has 11-fold lower potency compared to
the potent mPGES-1 inhibitor 8a (Table 2). Next, fluorinated amide
derivatives 8f–h were introduced in order to improve metabolic
stability. Among them, 8h gave adequate metabolic stability and
satisfactory mPGES-1 enzyme and cell potency. Further, introduc-
tion of simple aniline derived amide 8i provided single digit
enzyme and cell potency. However, it showed poor stability in
HLM and adequate stability in GPLM. Next, 4-fluorophenyl derived
amides 8j, 8k and 4-trifluoromethylphenyl derived amides 8l–n
unveiled single digit enzyme potency and acceptable A549 cell
potency along with more than adequate metabolic stability
(Table 2). In addition, para- and meta-substituted cyclopropy-
lphenyl amides 8o and 8p33 also provided adequate metabolic sta-
bility along with satisfactory enzyme and cell potency (IC50s: <20
nM). The introduction of di-substituted aryl amides such as, 2-flu-
oro-4-trifluoromethylphenyl derived amide 8q and 4-fluoro-3-tri-
fluoromethylphenyl derived amide 8r furnished significant
mPGES-1 potency (IC50s: 3.7 and 4.7 nM) and acceptable metabolic
stability in liver microsomes. Among the substituted pyridine
derived amides 8s–w tested, 8s (IC50: 6.7 nM) and 8w (IC50: 13
nM) displayed poor metabolic stability even though they possessed
satisfactory mPGES-1 potency. In contrast, analogs 8t–v provided
reasonable enzyme and cell potency along with adequate meta-
bolic stability in comparison with other analogs (Table 2).
Having identified several mPGES-1 inhibitors with satisfactory
enzyme, A549 cell potency and adequate metabolic stability, com-
pounds such as 8h, 8l–n and 8t were further evaluated for PGE2
release human whole blood (HWB) potency and most relevant
human cytochrome P450 (CYP) inhibition study. Among these, only
compounds 8h, 8l–n were demonstrated good HWB potency
(Table 3). Further, compounds 8n and 8u having pyridine ring in
the scaffold strongly inhibited CYP isoforms 3A4 and 2C9, whereas
8h, 8p and 8t revealed higher CYP2C9 and CYP2C19 liability at 10
mM concentration which is not desirable. Other potent mPGES-1
inhibitors 8l and 8m strongly inhibited only CYP2C9 isoform.
Potent compounds 8l–n were further evaluated for hERG activity
and displayed moderate activity in the hERG channel35 (patch
clamp assay, 38–56% inhibition @ 10 mM test concentration), sug-
gesting lower likelihood of QTc prolongation effect36 in humans
as disclosed in Table 3.
Compd
R1
X
Y
mPGES-1
Met. stability
(% remaining)c
IC50 (nM)a,b
HLM
GPLM
7a
7b
7c
d7d
7e
7f
7g
7h
7i
Isopentyl
Cl
Cl
F
Cl
Cl
Cl
Cl
F
Cl
Cl
Cl
Cl
N
N
C
N
C
N
C
C
C
N
C
C
82
13
11
12
26
157
58
22
10
–
–
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexyl
Cyclohexyl
4F-Benzyl
4F-Benzyl
4F-Phenyl
2F-Phenyl
55
19
19
–
0.4
0.9
29
–
–
–
–
–
66
75
–
78
85
7j
4CF3-Phenyl
4CF3-Phenyl
3CF3-Phenyl
6.5
9.4
4.6
7k
95
79
45
60
d7l
a
MF-63 (1) was used as a positive control in this experiment. See Refs. 3a, 10 and
14 for the literature reported potency.
IC50 values are derived from graphs plotted with data from a minimum of two
experiment in duplicates.
Percentage of test compound remaining after 60 min incubation with liver
microsomes (human and guinea pig) at 37 °C. MS experiment was conducted in
triplicates (see Supporting info (SI) for details.
b
c
d
A549 cell potency of 7d (cell IC50: 39 nM) and 7l (cell IC50: 18 nM).
IC50s < 10 nM except 7h which gave slightly lower enzyme potency
(IC50: 22 nM). These compounds revealed favorable metabolic sta-
bility in human and guinea pig liver microsomes. Couple of com-
pounds from this series, 7d and 7l were further evaluated for
PGE2 release cell potency (A549)30 and the cell IC50s were exempli-
fied as 39 nM and 18 nM, respectively (Foot note in Table 1). The
metabolically stable and potent compound 7l was further assessed
in the LPS-stimulated human whole blood (HWB) assay30 and cyto-
chrome P450 (CYP) assay. Thus, 7l displayed poor human whole
blood potency (HWB IC50: 1890 nM) and no CYP isoforms liability
against CYP3A4, CYP2C9 and CYP2C19 (<50% inhibition at 10 mM
concentration) tested (Table 3).
Few aniline derived amides 7j–l exhibited poor intrinsic solubil-
ity probably attributed due to its near planar tricyclic scaffold.31
Consequently, in order to improve compound solubility while
maintaining the overall molecular size and similar shape of
furan-fused benzo[d]imidazole series 7, we sought to reduce the
overall aromatic ring count by increasing the sp3 carbon count in
our new design through the saturation of furan ring of benzimida-
zole system.32 This modification led to dihydrofuran-fused benz-
imidazole 8, which expected to offer favorable enzyme, cell,
human whole blood potency and improved solubility. The dihydro-
furan-fused benzimidazole analogs 8a–w (Table 2) were prepared
starting from advanced intermediate 11 as shown in Scheme 2. The
intermediate 11 was alkylated using methallyl chloride in the pres-
ence of K2CO3 in DMF at 80 °C to afford compound 18 in 55% yield.
Claisen rearrangement of 18 in N,N-dimethylaniline and subse-
quent treatment with formic acid at 100 °C gave dihydro benzofu-
ran derivative 19,33 followed by nitro reduction in Fe/aq.HCl to
afford diamine compound 20. Isothiocyanate 15,28 prepared from
the corresponding aryl aniline using thiophosgene and diisopropy-
lethyl amine, reacted with diamine 20 in the presence of N,N0-
Based on the preliminary data disclosed in Tables 2 and 3, com-
pounds 8l and 8m were chosen for further profiling due to its
favorable enzyme, cell and HWB potency, acceptable CYP inhibi-
tion and metabolic stability, and moderate hERG liability compared
to other potent mPGES-1 inhibitors. Therefore, the identified pre-
clinical leads (8l and 8m) were further evaluated in guinea pig
(in vivo efficacy model species) and showed single digit enzyme
potency (GPIC50s: 2.6 and 6.3 nM) and adequate whole blood
potency (guinea pig whole blood IC50 of 8m: 222 nM). In addition,
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N. Muthukaman et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
5
Table 2
SAR of dihydrofuran-fused benzo[d]imidazole.
Compd
R1
X
Y
mPGES-1 IC50 (nM)a,b
A549, 2% FBS PGE2 IC50 (nM)c
Metabolic stability
(% remaining)d
HLM
GPLM
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
e8o
e8p
8q
8r
Cyclohexylmethyl
Cyclopentylmethyl
Cyclopropylmethyl
Cyclopropylmethyl
Cyclohexyl
4,4-Difluorocyclohexyl
CF3CH2–
CF3CF2CH2–
Phenyl
4F-phenyl
4F-phenyl
4CF3-Phenyl
4CF3-Phenyl
4CF3-Phenyl
4Cy-Phenyl
3Cy-Phenyl
2F, 4CF3-Phenyl
4F, 3CF3-phenyl
6CH3O-3-Pyridyl
6CHF2O-3-Pyridyl
6CF3-3-Pyridyl
5Cl-2-Pyridyl
2,6-Dimethyl-3-pyridyl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
N
C
N
C
N
C
C
C
C
C
C
C
C
N
C
C
N
N
C
C
C
C
C
2.2
2.3
25
12
6.3
47
7.8
–
–
47
12
–
37
1
89
38
3
0.4
6
71
41
1
–
–
23
–
36
61
37
59
73
97
87
89
86
89
100
98
6
29
53
65
100
100
65
78
100
58
73
85
73
44
52
34
89
9
6.2
4.1
3.5
2.8
3.7
3.9
5.8
4.2
7.7
3.7
4.7
6.7
20
12
4.1
11
20
4.4
10
7.2
4.3
19
12
–
Cl
F
Cl
F
F
Cl
Cl
Cl
F
Cl
F
8s
8t
8u
8v
8w
–
33
20
29
–
71
75
72
29
17
21
13
Cl
a
b
c
MF-63 (1) was used as a positive control in this experiment. See Refs. 3a, 10 and 14 for the literature reported potency.
IC50 values are derived from graphs plotted with data from a minimum of two experiment in duplicates.
IC50 values represent the concentration to inhibit 50% of PGE2 relative to vehicle control and derived from graphs plotted with data from a minimum of two experiments
in duplicates.
d
Percentage of test compound remaining after 60 min incubation with liver microsomes (human and guinea Pig). At 37 °C. MS experiment was conducted in triplicates (see
Supporting info (SI) for details. HLM: human liver microsomes; GPLM: guinea pig liver microsomes.
e
See Ref. 34 for details.
Table 3
leads 8l and 8m were found to be >1000-fold selective for mPGES-
HWB, CYP and hERG data of selected mPGES-1 inhibitors.
1 over COX-1, COX-2, mPGES2 and cPGES enzymes. As established
earlier for other known mPGES-1 inhibitors,13–21 our leads 8l and
8m were not active against rat and mouse enzymes as illustrated
in Table 4. Further, both leads demonstrated more than adequate
metabolic stability, favorable CYP inhibition except CYP2C9 liabil-
ity, high plasma protein binding (PPB) and low PAMPA permeabil-
ity.30 In general, most of the approved COX-2 inhibitors (Coxibs)
were having adequate CNS penetration which contributed to its
analgesic activity.37 The lead compound 8m tested for CNS pene-
tration revealed sufficient brain penetration and the brain to
plasma (B/P) ratio 0.22 was obtained. Hence, CNS penetration of
8m may positively contribute to its analgesic activity in the effi-
cacy model. Leads 8l and 8m were further evaluated against wide
range of receptors, enzymes assays and ion channel binding (CEREP
safety screen panel) to understand off-target liability.38 The CEREP
safety data of 8l and 8m revealed moderate binding against Na+,
Clꢀ channels, 5-LO (50–65% inhibition @ 10 mM concentration)
and strong binding activity against benzodiazepines (BZD) as dis-
closed in Table 4. The BZD potency of 8l and 8m had only ꢁ30-fold
margin over their mPGES-1 enzyme potency, which probably may
Compd
HWB IC50 (nM)a,b
CYP% inhibition @
10 mM
hERG% inhi. @10 mMd
concentrationc
3A4
2C9
2C19
7l
1890
302
234
275
164
–
15
0.3
16
42
87
39
34
64
40
81
82
72
57
69
77
75
40
88
41
51
33
85
55
39
–
–
51
56
38
–
8h
e8l
e8m
8n
8p
8t
1335
–
–
–
8u
a
MF-63 (1) was used as a positive control in this experiment. See Refs. 3a, 10 and
14 for the literature reported potency.
Lipopolysaccharide (LPS) stimulated human whole blood (HWB) cell assay. IC50
values represent the concentration to inhibit 50% of PGE2 relative to vehicle control
and minimum of two experiments in duplicates.
b
c
Cytochrome P450 (CYP)% inhibition as compared to control (no inhibitor) and
conducted in triplicates (see SI for details).
d
For hERG assay, see Ref. 35.
For CYP1A2 and CYP2D6 data, see Table 4.
e
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6
N. Muthukaman et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Table 4
Summary of in vitro data of pre-clinical lead 8l and 8m.
Parametersa
8l
8m
In vitro pharmacology:
mPGES-1 hIC50
3.7 nM
3.9 nM
A549 cell IC50
4.4 nM
10 nM
hWBA
234 nM
275 nM
Guinea pig IC50
2.6 nM
6.3 nM
Guinea pig WBA
Rat mPGES-1 inhibition
Mouse mPGES-1 inhibition
COX-1 inhibition
COX-2 inhibition
mPGES-2 inhibition
cPGES inhibition
NT
222 nM
4.5% @10 mM
10.4% @ 10 mM
11.8% @ 10 mM
0% @ 10 mM
16.2% @ 10 mM
1.4% @ 10 mM
14.7% @10 mM
8.2% @ 10 mM
44.2% @ 10 mM
3.2% @ 10 mM
11.8% @ 10 mM
0.01% @ 10 mM
ADME properties
Metabolic stability (% remaining), H/GPig/R/M/D/Mk
CYP (% inhibition @10 mM), 1A2/2D6/3A4/2C9/2C19
PPB (% bound), H/R/G.Pig
97/65/88/96/90/85
17/5/16/82/41
>99.5/99.1/>99.5
87/78/84/92/92/84
23/18/42/72/51
99.2/>99.5/>99.5
Rat CNS b/p ratio
NT
NT
0.22
0.13 (low)
PAMPA (Pe x 10ꢀ6)cm/s
In vitro safety properties: hERG inhibition (Patch clamp)
POR (CEREP panel data; Potential off-target liability)
51%@ 10 mM
56%@ 10 mM
Na+ channel: 57%@ 10 mM (IC50: 1.4 mM)
BZD (peripheral): 80%@10 mM (IC50: 120 nM)
5-LO: 63%@ 10 mM (IC50: 2.6 mM)
EP3(h) agonist: 51%@10 mM
FP (h) agonist: 59%@10 mM
Na+ channel: 67%@10 mM (IC50: 2.4 mM)
Cl- channel: 62%@10 mM (IC50: 6.0 mM)
BZD (peripheral): 86%@10 mM (IC50: 110 nM)
5-LO: 58%@10 mM (IC50: 6.1 mM)
A3(h) agonist: 76%@10 mM
FP (h) agonist: 61%@10 mM
b
cSolubility data
Solubility in DMSO
20 mg/mL
0.3 mcg/mL
0.6 mcg/mL
Nil
25 mg/mL
0.9 mcg/mL
0.6 mcg/mL
Nil
Solubility at FaSSIF (pH 6.0)
Solubility at FeSSIF (pH 5.2)
Solubility in acetate buffer (pH 4.5)
0.1 N HCl
0.1 mcg/mL
0.2 mcg/mL
NT: Not tested.
a
See supporting information for experimental procedure.
POR data presented here for 8l and 8m, which showed >50% inhibition at 10 mM test concentration against receptors, ion channels and enzyme targets. See Ref. 37.
Fasted state simulated intestinal fluid (FaSSIF) and Fed state simulated intestinal fluid (FeSSIF).
b
c
induce some toxicity during compound development. As intrinsic
using methyl cellulose (MC) suspension revealed dose proportional
increase in Cmax and mean AUC as shown in Table 5. Similarly, a
dose range oral PK studies of 8m (10 and 30 mg/kg) in guinea
pig provided gradual increase in Cmax and mean AUC with satura-
tion at 100 mg/kg. The dog PK study39 of 8m (10 mg/kg) displayed
increase in Cmax, mean AUC and very slow absorption (Tmax = 12 h)
in comparison to rodent data. The intravenous and oral PK study of
8m in cynomolgus monkey39 (1 mg/kg i.v, and 10 mg/kg oral)
revealed lower clearance (Cl = 8.03 mL/min/kg), volume of distri-
bution (Vz = 1.7 L/kg), lower half-life (T1/2 = 2.5 h), and 78%
bioavailability in comparison to rat data and comparable Cmax
and mean AUC was observed with respect to dog PK data. Thus,
compound 8m demonstrated satisfactory PK data across species.
Having established favorable pharmacokinetics in rat, guinea
pig, dog and monkey, the advanced lead 8m was further evaluated
for in vivo efficacy in acute pain model.30 The lead compound 8m
was studied at 3, 10 and 30 mg/kg in LPS-induced hyperalgesia
pain model in guinea pig and the results are summarized in
solubility is an important parameter for drug development, current
leads 8l and 8m were further subjected to solubility study and
revealed moderate to low solubility in the aqueous media as
shown in Table 4. Although both 8l and 8m provided comparable
in vitro pharmacology and pharmacokinetics profile (DMPK), we
chose compound 8m for further profiling due to slightly lesser
lipophilicity and molecular weight.
After accomplishing favorable in vitro properties, advanced lead
8m was further assessed for oral pharmacokinetics (PK) in rat, gui-
nea pig, dog and cynomolgus monkey, and the results were sum-
marized in Table 5. Lead 8m was found to have low intravenous
half-life (T1/2 = 1.1 h) in rat (1 mg/kg dose), as a result of high clear-
ance (Cl = 37 mL/min/kg), low volume of distribution (Vz = 3.6 L/
kg), respectively. Besides, 8m demonstrated 100% oral bioavailabil-
ity (%F), acceptable Cmax and mean AUC along with adequate CNS
brain penetration (Tables 4 and 5) in 10 mg/kg oral dose in rat.
In addition, dose ranging study of 8m (30 and 100 mg/kg) in rat
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N. Muthukaman et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
7
Table 5
Oral pharmacokinetic (PK) data of 8m in rat, guinea pig, dog and cynomolgus monkey.
Parametersa
Rat (n = 3)b,c
Guinea Pig (n = 3)d
Dog (n = 3)e
Cyno monkey (n = 3)f
Dose (mg/kg)
Cmax (ng/mL)
AUC0-24 (ng.h/mL)
Tmax (h)
% F
T1/2 (h)
10
30
100
5546 980
107911 24201
8
–
–
–
–
10
426 71
5078 983
4
ND
ND
ND
ND
30
742 104
11628 2176
4
–
–
–
–
100
736 130
11675 2719
2
–
–
–
–
10
10
546 88
6505 103
2
100
1.12 0.17
2531 652
32370 13656
2
100
–
1093 105
21998 3045
12
ND
ND
ND
ND
908 127
16696 9907
6
78
2.49 0.63
8.03 1.66
1.67 0.112
CL (mL/min/kg)
Vz (L/kg)
37
2
–
–
3.59 0.34
-: not applicable; ND: not determined.
a
Cmax, AUC0-24, Tmax, %F, T1/2, CL and Vz were determined in male Sprague-Dawley rats. Rat and cynomolgus monkey i.v dose is 1 mg/kg.
b
c
d
e
f
Vehicle for rat Oral dosing- 0.5% methylcellulose (MC) suspension; Vehicle for rat i.v- 20% NMP + 20% Ethanol + 60% PEG 200). The data represented is mean SD (n = 3).
Rat CNS b/p ratio = 0.22 (brain concentration: 58.9 ng/mL/plasma concentration: 268.9 ng/mL).
Vehicle for guinea pig oral dosing- 0.5% methylcellulose suspension. The data represented is mean SD (n = 3).
Vehicle for beagle dog oral dosing-2.5
lL/mL Tween 80 + 0.5 (w/v) methyl cellulose (MC) suspension. See Ref. 39
Vehicle for cynomolgus monkey oral dosing-2.5 mL/mL Tween 80 + 0.5 (w/v) methyl cellulose (MC) suspension. Vehicle for cynomolgus monkey i.v dosing-10% NMP + 10%
ethanol + 10% PEG + 70% premix solvent (v/v mixture of 3:2 PEG200: Milli-Q water). See Ref. 39.
and centrally mediated PGE2 synthesis13,40 and showed efficient
analgesic activity in the LPS-induced hyperalgesia pain model
when administered orally.
In conclusion, we have demonstrated the optimization of furan
and dihydrofuran-fused tricyclic benzo[d]imidazole analogs as
mPGES-1 inhibitor with favorable enzyme and cell potency. The
most potent analogs 8l and 8m displayed satisfactory in vitro
potency in human, guinea pig enzymes and selectivity over COX-
1, COX-2, mPGES-2 and cPGES enzymes. Compounds 8l and 8m
were metabolically stable in across species tested (human, guinea
pig, mouse, rat, dog and monkey liver microsomes) and had liabil-
ity only for CYP2C9, CYP2C19, and hERG channel. No significant
off-target liability for compounds 8l and 8m were observed in
CEREP panel assay except BZD. The advanced lead 8m demon-
strated adequate CNS penetration and satisfactory oral PK in rat,
guinea pig, dog and cynomolgus monkey along with high oral
bioavailability in rat and monkey. Further, lead 8m exhibited
in vivo efficacy in hyperalgesia pain model with ED50 of 14.3 mg/
kg. Since, current series suffer from CYP and hERG channel liabili-
ties, further SAR optimization is necessary to overcome these lia-
bilities without altering the core scaffold. Consequently, SAR
optimization of dihydrofuran-fused tricyclic benzo[d]imidazole
mPGES-1 inhibitors free from CYP and hERG liabilities will be
reported in the forthcoming publication.
Fig. 3. Analgesic effects of 8m in the guinea pig hyperalgesia pain model. Data are
expressed as percentage of hyperalgesia, with the naive group (injected intraplan-
tarly with saline) as 0% and the vehicle-treated LPS-injected group as 100%. Results
are shown as Mean S.E.M. (n = 5–8/group).
Table 6
Plasma concentration of 8ma at PD time point.
Dose
(mg/kg, po, od)
% Hyperalgesia
inhibition
Plasma concentration@
PD time point (ng/mL)b
Hyperalgesia
ED50 (mg/kg)
Acknowledgements
3
10
30
0
42
61
43
116
192
We thank Drs Sravan Mandadi and Sanjib Das for the review of
this manuscript and valuable inputs. We also thank scientists from
the analytical support group for their help in compound
characterization.
14.3
a
Guinea pig whole blood IC50: 222 nM.
Concentrations are means of n = 5–8 animals per dose group. The data repre-
b
sented is from a single experiment. Study protocol is provided in the SI.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2017.10.062.
Fig. 3 and Table 6. Injection of LPS into the plantar region of guinea
pig right hind paw caused a significant increase in thermal hyper-
algesic response compared to saline injected animals. The lead
compound 8m was significantly inhibited hyperalgesic response
in a dose-dependent manner with maximum inhibition of 61% at
30 mg/kg in comparison with NSAID standard, Naproxen (Fig. 3).
The calculated ED50 was found to be 14.3 mg/kg. As depicted in
Table 6, the plasma concentration was measured at 8.5 h (pharma-
codynamics time point) post compound treatment 8m (30 mg/kg)
and was found to be 192 ng/ml (equivalent to 371 nM). This is
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