Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC)

Article abstract of DOI:10.1016/j.bmcl.2019.03.039

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

Full text of DOI:10.1016/j.bmcl.2019.03.039

Accepted Manuscript
Accelerating the discovery of DGAT1 inhibitors through the application of par-
allel medicinal chemistry (PMC)
Yang Yu, Zhicai Wu, Zhi-Cai Shi, Shuwen He, Zhong Lai, Timothy A. Cernak,
Petr Vachal, Liu Min, Jian Liu, Qingmei Hong, Tianying Jian, Deodial
Guiadeen, Arto Krikorian, Donald M. Sperbeck, Andreas Verras, Lisa M.
Sonatore, Beth A. Murphy, Judyann Wiltsie, Christine C. Chung, Judith N.
Gorski, Jinqi Liu, Jianying Xiao, Michael Wolff, Sharon X. Tong, Maria
Madeira, Bindhu V. Karanam, Dong-Ming Shen, James M. Balkovec, Robert J.
De Vita, Shirly Pinto, Ravi P. Nargund
PII:
S0960-894X(19)30177-5
https://doi.org/10.1016/j.bmcl.2019.03.039
BMCL 26353
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 January 2019
19 March 2019
25 March 2019
Please cite this article as: Yu, Y., Wu, Z., Shi, Z-C., He, S., Lai, Z., Cernak, T.A., Vachal, P., Min, L., Liu, J., Hong,
Q., Jian, T., Guiadeen, D., Krikorian, A., Sperbeck, D.M., Verras, A., Sonatore, L.M., Murphy, B.A., Wiltsie, J.,
Chung, C.C., Gorski, J.N., Liu, J., Xiao, J., Wolff, M., Tong, S.X., Madeira, M., Karanam, B.V., Shen, D-M.,
Balkovec, J.M., De Vita, R.J., Pinto, S., Nargund, R.P., Accelerating the discovery of DGAT1 inhibitors through
the application of parallel medicinal chemistry (PMC), Bioorganic & Medicinal Chemistry Letters (2019), doi:
https://doi.org/10.1016/j.bmcl.2019.03.039
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Accelerating the Discovery of DGAT1 Inhibitors through the
Application of Parallel Medicinal Chemistry (PMC)
Yang Yu*, Zhicai Wu, Zhi-Cai Shi, Shuwen He, Zhong Lai, Timothy A. Cernak, Petr
Vachal, Liu Min, Jian Liu, Qingmei Hong, Tianying Jian, Deodial Guiadeen, Arto
Krikorian, Donald M. Sperbeck, Andreas Verras, Lisa M. Sonatore, Beth A. Murphy,
Judyann Wiltsie, Christine C. Chung, Judith N. Gorski, Jinqi Liu, Jianying Xiao, Michael
Wolff, Sharon X. Tong, Maria Madeira, Bindhu V. Karanam, Dong-Ming Shen, James
M. Balkovec, Robert J. DeVita, Shirly Pinto and Ravi P. Nargund
Discovery and Preclinical Sciences, Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
The parallel medicinal chemistry (PMC) was effectively applied to accelerate the
optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors.
Through a highly collaborative and iterative library design, synthesis and
testing, a benzimidazole lead was rapidly and systematically advanced to a
highly potent, selective and bioavailable DGAT1 inhibitor with the potential for
further development.
Keywords:
Parallel medicinal chemistry
High throughput purification
DGAT1 inhibitor
Triglyceride
2009 Elsevier Ltd. All rights reserved.
Benzimidazole
ACAT1
A2A receptor
Cyclohexane acetic acid
Lipid tolerance test
Pharmacokinetics
The pharmaceutical industry has been under increased pressure to deliver drug candidates
in a more cost-effective and timely manner.1 Pharma companies are increasingly
developing and applying innovative capabilities to make better molecules faster. Many
enabling chemistries and technologies were developed to improve the access to target
molecules with expanded chemical diversity. Parallel medicinal chemistry (PMC) and
high throughput purification are also routinely applied to reduce the design-make-test
cycle time.2
We have effectively applied a highly collaborative PMC model to champion the design,
synthesis and purification of target molecules to accelerate drug discovery programs.3 As
a case study, here we describe how we accelerated the optimization of diacylglycerol O-
acyltransferase I (DGAT1) inhibitors via the application of PMC from a benzimidazole
lead to a promising candidate with the potential for further development in less than one
and half years.
Obesity and diabetes have become perceivable threats to public health and national
interest.4 Over accumulation of triglycerides (TG) is one of the main causes of obesity
1

and diabetes.5, 6 During dietary fat absorption, dietary TG are digested to
monoacylglycerols in the gut and absorbed in small intestines. DGAT1, a transmembrane
protein, catalyzes the final step wherein TG are re-assembled from monoacylglycerols.7
Multiple pharmaceutical companies had executed DGAT1 projects intending to develop
novel small molecule drugs targeting human metabolic diseases.8 – 14 Some of those
inhibitors entered clinical trials for the treatment of obesity or type II diabetes.15
Most of the disclosed DGAT1 inhibitors contained a phenyl-cyclohexane acetic acid
moiety that is apparently critical for DGAT1 potency. Our DGAT-1 team developed a
benzimidazole lead series as exemplified by 1 and 2 in Figure 1. The representative
compounds 1 and 2 displayed strong potency against human and mouse DGAT1
isoforms, but with poor selectivity against ACAT1 (ACAT1 IC50 = 325 nM for 1 and 485
nM for 2) which could cause adrenocortical toxicities.16
Figure 1. Benzimidazole lead series
To address the ACAT1 selectivity issue, we systematically studied each structural
component of the lead class. Lead Optimization (LO) team explored the structure-
activity-relationship (SAR) of B-ring through traditional singleton synthesis. PMC
focused on investigating A, C and D rings by library screening. One of the diversified
libraries to explore the SAR of C-ring was exemplified in Scheme 1. The library was
synthesized by Suzuki coupling intermediate 3 with a variety of boronic acids or
boronates.
Scheme 1. Exploration of C-ring SAR a
a Reagents of condition: (a) 6-bromophenylaldehyde, potassium peroxymonosulfate,
DMF-water, 72%; (b) Boronic acids / pinacol boronates, Na2CO3, PdCl2(dppf), dioxane-
water, 90oC, 16 h.
Table 1. Selected examples of the C-ring library shown in Scheme 1
2

NT = Not tested due to low DGAT1 potency
Selected analogues in Table 1 showed that replacing the C-ring with pyridine not only
significantly improved DGAT1 potency (Compound 4 vs. 5 and Compound 9 vs. 6) but
also increased the ACAT1 selectivity (Compound 7 vs. 8 and compound 10 vs. 11).
Among these compounds, the IC50 ratio of human ACAT1 versus DGAT1 of compound
6 was > 500 folds. Compounds 6, 10, 11 and 12 with oxygen or nitrogen substitution at
the 2-position of the pyridine retained good human DGAT1 inhibiting activities. We
hypothesized that lowering LogD and increasing flexibility of the lead compound could
improve the selectivity against ACAT1 while maintaining good DGAT1 potency.
Moreover, compared with those with phenyl ring as C-ring, compounds with pyridine as
the C-ring had comparable selectivity against hERG channel.
Meanwhile, B-ring SAR explored by LO team showed that compounds with pyridine as
the B-ring had comparable profiles as phenyl ring, but exhibited superior bioavailability.
Thus, benzimidazole pyridyl-pyridyl N- and O-linked libraries were designed and
synthesized to explore the feasibility (Scheme 2).
To substitute the fluoro group on pyridyl-pyridyl scaffold, intermediate 14 was reacted
with 24 amino carboxylic acids or carboxylates via SNAr reaction. The resulting
carboxylate intermediates were hydrolyzed to furnish the N-linked analogues. Compound
14 was also used to produce the O-linked library by substituting the fluoro group with 20
diverse ester-containing alcohols or phenols and then hydrolyzing the ester to acid to
yield the products.
Scheme 2. Design and synthesis of benzimidazole pyridyl-pyridyl N- and O-linked
libraries a
3

a Reagents and conditions: (a) (6-fluoropyridin-3-yl)boronic acid, Na2CO3, PdCl2(dppf), DMF-
water, 80oC, 16 h, 69%; (b) 4-chlorobenzene-1,2-diamine, potassium peroxymonosulfate, DMA-
Water, 16 h, 70%; (c) For amino building blocks with carboxylic acids or carboxylates, NaHCO3,
NMP, 110oC, 16 h; For phenols, K2CO3, NMP, 110oC, 20 h; For alcohols with carboxylates,
NaH, NMP, 110oC, 20 h; (d) For N-linked analogues with carboxylates, LiOH-H2O, MeOH-THF
(1:1), 50oC, 2 h; For O-linked analogues with carboxylates, one-pot, MeOH, ambient
temperature, 2 h.
Table 2. Profile of representative compounds of benzimidazole N-linked and O-linked
pyridyl-pyridyl libraries, N-linked analogues 15 – 23, O-linked analogues 24 - 32
hERG
binding
(Ki, M)
Human
DGAT1
IC50 (nM)
Mouse
DGAT1
IC50 (nM)
Human
ACAT1
IC50 (nM)
LogD
(HPLC)
Mouse
LTT
D-ring
Comp
2.5
2.9
20
20
1.45
1.33
> 10000
> 10000
4.8
-96%
0%
15
16
12.12
4.2
4.5
4.5
21
33
36
1.51
1.56
1.43
> 10000
> 2000
> 2000
3.56
1.74
1.98
0%
17
18
19
-66%
-63%
5.4
9.6
48
84
1.37
1.30
1.48
1.29
> 2000
> 10000
> 2000
> 2000
3.75
11.89
5.22
-70%
NT
20
21
22
23
10.2
22.0
108
247
-62%
NT
> 60
0.7
1.3
1.5
1.7
2.6
3.1
1.4
4.4
2.8
5.0
6.3
11
1.44
1.49
1.42
1.24
1.39
1.35
971
1940
>2000
1718
1967
1652
8.14
1.36
NT
NT
24
25
26
27
28
29
5.39
-144%
-89%
-83%
-50%
20.05
3.52
10.75
4

3.5
3.6
5.3
24
30
36
1.16
1.19
1.16
>2000
>2000
>10000
20.23
18.98
6.54
-54%
-91%
-87%
30
31
32
NT = Not tested; Mouse lipid tolerance test (LTT) was measured after 18 hours at 10 mg/kg
single oral dosing.
Table 2 summarizes the representative compounds from these two libraries. N-linked
compounds 15 – 23 showed potent inhibition of human and mouse DGAT1. These
compounds generally have a clean off-target profile. All compounds had > 2000 nM
ACAT1 IC50 and some of them exhibited > 10000 nM ACAT1 IC50. Thus, the N-linked
pyridyl-pyridyl series substantially improved the selectivity against ACAT1.
Compound 15 had the best human DGAT1 potency (IC50 = 2.5 nM) and the best
selectivity against ACAT1 (> 4000-fold) in the N-linked series. An in-vivo mouse lipid
tolerance test (LTT) was utilized to evaluate pharmacodynamics efficacies by comparing
the reduction of lipid excursions of the synthesized compounds with vehicle and a
positive control compound.17 Compound 15 displayed an excellent in-vivo efficacy in
mouse LTT with 96% reduction of lipid excursion after 18 hours at 10 mg/kg single oral
dose. Compounds 18, 19, 20 and 22 had modest lipid excursion reductions (> 60% after
18 hours at 10 mg/kg single oral dosing) in mouse LTT. In addition, compounds 16 and
17 did not show any mouse LTT efficacy and compound 21 had high CYP 2C8 inhibition
(IC50 = 2.5 nM). Unfortunately, none of these analogues met the desired selectivity
against the hERG channel (Ki > 30 M) except for compound 23, which lacked strong
mouse DGAT1 potency and was not tested in mouse LTT. Many follow-up analogues
were synthesized and tested in singleton or library format. However, it was challenging to
identify compounds that balanced DGAT1 potency and hERG selectivity.
On the other hand, compounds 27, 30 and 31 in the O-linked library showed improved
selectivity against hERG channel. By calculating the basicity of the most basic group of
the O-linked scaffold (calculated pKa ~ 3.0) versus that of the N-linked scaffold
(calculated pKa > 5.0), we arrived at the hypothesis that the low basicity of the O-linked
analogues contributed to this improvement.
Moreover, the O-linked pyridyl-pyridyl analogues generally show better human and
mouse DGAT1 inhibitory activity than the N-linked analogues. HPLC measured LogDs
of the O-linked pyridyl-pyridyl analogues were comparable with those of the N-linked
compounds. Among these selected O-linked analogues, compound 24 had poor ACAT1
selectivity (IC50 =971 nM), in spite of potent human DGAT1 inhibition (IC50 < 1 nM).
Compound 25 had unacceptable solubility (<1 M at pH = 7). Compounds 26, 28 and 32
demonstrated robust lipid excursion reductions in the mouse LTT but had poor hERG
selectivity. Compounds 27 and 31 showed strong in-vivo efficacy and improved hERG
selectivity (both had > 89% lipid excursion reductions after 18 hours at 10 mg/kg single
5

oral dosing in mouse LTT). Compounds 29 and 30 displayed acceptable selectivity
against ACAT1 and hERG with modest lipid excursion reductions in mouse LTT.
In an effort to address these issues, we fixed the D-ring pharmacophores of these
analogues (26, 27, 28, 29, 30, 31 and 32) and explored the A-ring SAR through seven
individual libraries (Figure 2) with a similar set of substituted benzimidazoles or
azabenzimidazoles as exhibited in Table 3.
Figure 2. A-ring screening of pyridyl-pyridyl series
Libraries with D-ring pharmacophores from compounds 27, 29, 30, 31 and 32 did not
result in compounds with good in-vivo efficacies and improved hERG selectivity. In
contrast, screening the A-ring with cis- and trans-oxy-cyclohexane carboxylic acids
derived from compounds 26 and 28 as the D-ring resulted in several good compounds
with balanced selectivity, off-target-activities and in-vivo efficacy in mouse LTT.
Unfortunately, we found that the carboxylic acid on the cyclohexane ring of those
compounds can undergo a cis/trans epimerization in-vivo.18
One plausible explanation for such isomerization is that the acyl-CoA covalently interacts
with the carboxylic acid group and causes the cis/trans isomerization through a
cyclohexylidene (acyl-CoA) methanolate intermediate.19 We devised several strategies to
address this issue. First, we substituted the hydrogen at the α-position of the carboxylic
acid on the cyclohexane ring with a methyl group, which blocks the epimerization.
Second, we replaced carboxylic acid with acetic acid on the cyclohexane ring to eliminate
the epimerization.
While keeping the oxy-cyclohexane α-methyl carboxylic acid or oxy-cyclohexane acetic
acid as the D-ring, we applied focused libraries to rapidly evaluate these two strategies.
Gratifyingly, we did not observe isomerization during in-vitro hepatocyte incubation
study or in-vivo mouse LTT study. The compounds with the oxy-cyclohexane α-methyl
carboxylic acid (both cis and trans), however, had lower in-vivo efficacy in mouse LTT
than that of the corresponding oxy-cyclohexane acetic acid analogues. Profile of the
focused library of cis oxy-cyclohexane acetic acid analogues is summarized in Table 3
due to their overall superior in-vitro and in-vivo experimental data to the corresponding
trans isomers.
Scheme 3. Synthesis of pyridyl-pyridyl cis oxy-cyclohexane acetic acid library a
6

a Reagents and conditions: (a) substituted benzene or pyridine diamines, potassium
peroxymonosulfate, 3% HOAc/DMF, 100oC, overnight; (b) LiOH-H2O, DMF, ambient
temperature, overnight.
Table 3. Profile of A-ring pyridyl-pyridyl cis oxy-cyclohexane acetic acid library,
compounds 34 – 44
hERG
binding
(Ki, M)
Human A2A
cAMP IC50
(M)
Human
DGAT1
IC50 (nM)
Mouse
DGAT1
IC50 (nM)
Human
ACAT1
IC50 (nM)
Mouse
LTT
Comp
1.3
1.6
1.7
2.1
1.7
1.5
2.6
2.3
942
970
3.0
NT
NT
NT
NT
NT
NT
NT
NT
34
35
36
37
4.1
> 2000
606
19.0
3.8
2.4
3.2
3.6
5.2
7.0
11.6
3.2
5.9
17.8
5.2
9.5
9.8
> 2000
1629
8.2
8.6
0.42
NT
-109%
NT
38
39
40
41
42
43
> 10000
> 2000
> 2000
> 2000
2.7
0.43
0.45
0.97
1.20
-63%
-92%
-92%
-96%
26.9
23.4
37.7
30.8
38.1
> 10000
> 60
0.49
NT
44
NT = Not tested; Mouse LTT was measured after 18 hours at 3 mg/kg single oral dosing.
Although most of the analogues had IC50 < 10 nM against human or mouse DGAT1, only
compounds 41, 42 and 43 had acceptable selectivity against both human ACAT1 (IC50 >
2000 nM) and the hERG channel (Ki ~ 30 M). These three compounds significantly
reduced lipid excursion (> 90%) in the mouse LTT after 18 hours at 3 mg/kg single oral
dose. We advanced them to an in-vitro safety pharmacology screening against a panel of
known biological targets to identify off-target liabilities. Unfortunately, all of them
showed unacceptable activity against human Adenosine IIa (A2A) receptors. We then
tested 30 representative compounds from the O- or N-linked benzimidazole pyridyl-
pyridyl series in an A2A cAMP functional assay. All of them showed activity against the
human A2A receptor.
7

Collaborating with Computational Modeling and Informatics (CM&I) group, we studied
the binding model of benzimidazole pyridyl-pyridyl molecules with A2A receptors and
found that the C-ring played a critical role in the binding interaction. The docking model
indicated that the nitrogen on the pyridine formed a hydrogen bond with amino acid
residue Tyr 271 of the A2A receptor, as well as the aromatic pyridine ring interacted with
Leu 167 of the A2A receptor through hydrophobic interactions.
We therefore designed and synthesized libraries and singletons, which used a variety of
piperidine or spiropiperidine derivatives to replace the C-ring pyridine in an effort to
improve the A2A selectivity.20, 21 Several representative compounds were tested in the A2A
binding assay. The results showed that these compounds (e.g. 45 and 46) not only had
high selectivity against A2A and ACAT1, but also exhibited strong DGAT1 inhibitory
potency (Figure 3).
Figure 3. Profile of spiropiperidine or piperidine as the C-ring of benzimidazole series
Encouraged by such a profile, we designed a focused library to explore the A-ring SAR
with piperidine as the C-ring and oxy-cyclohexane acetic acid as the D-ring (Scheme 4).
Both cis and trans oxy-cyclohexane acetic acid libraries were synthesized and tested.
Only the profile of trans isomers is summarized in Table 4 for their overall better in-vitro
and in-vivo experimental data than those of the corresponding cis isomers.
Scheme 4. Synthesis of A-ring pyridyl-piperidinyl trans oxy-cyclohexane acetic acid
library
a Reagents and conditions: (a) substituted benzene or pyridine diamines, potassium
peroxymonosulfate, 3% HOAc/DMF, 80oC, overnight; (b) LiOH-H2O, MeOH - THF (1:1),
ambient temperature, 3 h.
Table 4. Profile of A-ring pyridyl-piperidinyl trans oxy-cyclohexane acetic acid library,
compounds 48 - 58
hERG
binding
(Ki, M)
Human A2A
cAMP IC50
(M)
Human
DGAT1
IC50 (nM)
Mouse
DGAT1
IC50 (nM)
Human
ACAT1
IC50 (nM)
Mouse
LTT
Comp
48
2.0
4.6
> 10000
4.9
1.80
-57%
8

3.1
4.1
6.5
8.0
22.0
11.0
46.0
21.4
> 10000
> 10000
> 10000
>10000
4.5
4.1
0.68
0.52
3.48
0.91
NT
49
50
51
52
-65%
-84%
-92%
40.7
10.7
15.2
23.6
26.1
50.5
61.3
442.5
42.1
125
528
78
> 10000
> 10000
> 10000
> 10000
> 10000
NT
25.7
12.0
3.0
> 10.0
NT
-85%
NT
53
54
55
56
57
58
NT
NT
20.5
NT
NT
NT
271
1908
NT
NT
NT
NT
NT
NT = Not tested; Mouse LTT was measured after 18 hours at 3 mg/kg single oral dosing.
Analogues 48 – 58 had excellent selectivity against human ACAT1 (IC50 > 10000 nM).
Compounds 48, 49, 50 and 52, however, failed to meet the hERG and A2A selectivity
criteria (Ki > 30 M for hERG channel and IC50 > 2 M for A2A receptor). Compounds
51 and 53 displayed acceptable DGAT1 activity, selectivity and in-vivo efficacy.
Therefore, we advanced them to genetic toxicology studies. Compound 53 failed in a 3-
strain (TA1525, TA98, and TA100) microbial mutagenesis assay. Compound 51 passed
the Ames test over a concentration range of 30 to 5000 µg / plate.
Further in-vivo efficacy assessment showed that compound 51 significantly reduced lipid
excursion in dog LTT (100% at 1 mg/kg oral dosing). In pharmacokinetic studies,
compound 51 displayed good data in rat and dog (Table 5).
Table 5. Pharmacokinetic data of compound 51 in rat and dog a, b
PK parameters
F (%)
rat
dog
40
17
Cl (mL min-1 kg-1)
17.0
1.08
1.0
3.4
Vdss (L kg-1)
0.81
3.2
t
(h)
½
0.23
1.0
2.4
Cmax (M)
Tmax (h)
0.50
4.1
0.3
AUCn (M·h/(mg/kg))
9

a Compound dosed in Sprague-Dawley rats as a solution in EtOH/PEG400/H2O (10:50:40) at 1
mg/kg i.v. and 2 mg/kg p.o. b Compound dosed in beagles as a solution in EtOH/PEG400/water
(10:50:40) at 1 mg/kg, i.v., and as solution in 0.5% methylcellulose at 2 mg/kg, p.o.
In summary, parallel medicinal chemistry was effectively applied on a DGAT1 program
to expedite the SAR exploration and address program issues. Lowering LogD and
increasing flexibility of the benzimidazole scaffold solved the ACAT1 selectivity issue;
decreasing basicity of the molecule improved the selectivity against hERG channel;
replacing the aromatic C-ring with piperidine improved the A2A receptor selectivity;
substituting carboxylic acid on D-ring cyclohexane with acetic acid eliminated the
cis/trans isomerization problem. Through a highly collaborative and iterative library
design, synthesis and testing, we were able to efficiently discover highly potent and
selective DGAT1 inhibitors with the potential for further development.
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Graphical Abstract
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Accelerating the Discovery of DGAT1
Inhibitors through the Application of
Parallel Medicinal Chemistry (PMC)
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Yang Yu*, Zhicai Wu, Zhi-Cai Shi, Shuwen He, Zhong Lai, Timothy A. Cernak, Petr Vachal, Min Liu, Jian
Liu, Qingmei Hong, Tianying Jian, Deodial Guiadeen, Arto Krikorian, Donald M. Sperbeck, Andreas Verras,
Lisa M. Sonatore, Beth A. Murphy, Judyann Wiltsie, Christine C. Chung, Judith N. Gorski, Jinqi Liu, Jianying
Xiao, Michael Wolff, Sharon X. Tong, Maria Madeira, Bindhu V. Karanam, Dong-Ming Shen, James M.
Balkovec, Robert J. DeVita, Shirly Pinto and Ravi P. Nargund
12