Amide-based inhibitors of p38α MAP kinase. Part 1: Discovery of novel N-pyridyl amide lead molecules

Article abstract of DOI:10.1016/j.bmcl.2010.02.088

A novel series of N-pyridyl amides as potent p38α kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38α inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-α-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38α were evaluated against SAR findings and provided rationale for further development of this series of molecules.

Full text of DOI:10.1016/j.bmcl.2010.02.088

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2556–2559
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Amide-based inhibitors of p38
a
MAP kinase. Part 1: Discovery of novel
N-pyridyl amide lead molecules
*
Gregory R. Luedtke, Kurt Schinzel, Xuefei Tan , Richland W. Tester, Imad Nashashibi, Yong-jin Xu,
*
Sundeep Dugar, Daniel E. Levy , Joon Jung
Department of Medicinal Chemistry, Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of N-pyridyl amides as potent p38
similarities between the initial hit and a well-known imidazole pyrimidine series of p38
potencies within the newly discovered series were quickly improved by installation of an (S)-
a
kinase inhibitors is described. Based on the structural
inhibitors,
-methyl-
benzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to
p38 were evaluated against SAR findings and provided rationale for further development of this series
of molecules.
Received 2 January 2010
Revised 23 February 2010
Accepted 24 February 2010
Available online 10 March 2010
a
a
a
Keywords:
p38
Ó 2010 Elsevier Ltd. All rights reserved.
MAP
Kinase
Antiinflammatory
Modulation of cytokines has recently shown promise in the
treatment of diseases involving chronic inflammation. Support
AMG-548, BIRB-796 and SCIO-469).19–22 Recently, we described
our work surrounding the indole carboxamide-based lead
(Fig. 1).23 Herein, we wish to report our initial findings on a novel
class of heterocyclic amide inhibitors of p38
High throughput screening resulted in the identification of the
N-pyridyl amide 2 (Fig. 2), as an inhibitor of p38 . Recognizing
structural similarities with the well-known imidazole pyrimidine
series of p38
inhibitors, exemplified by 3 (Fig. 2),24 we developed
a working model in which the trans conformer of compound 2
binds to the p38
enzyme as shown in Figure 3.25 As illustrated,
1
for this approach is found in the utility of anti-TNF
a therapies
(Enbrel, Remicade) and anti-IL-1 treatment (Kineret).1–3 In
attempts to develop small molecule inhibitors with similar effects,
several kinase signaling pathways were examined over recent
years—including the p38 MAP kinase pathway.4–9
a.
a
The
a
isoform of p38 MAP kinase has been identified as a
a
control point which, when activated, translates multiple stimuli
to multiple responses. The end result is the release of a pro-inflam-
matory cassette of cytokines which includes interleukin-1b (IL-1b),
a
the pyridine ring makes the requisite hinge contact, while the
4-fluorobenzyl moiety occupies the hydrophobic pocket. Both
hydrogen bond interactions to the hinge amino acid Met-109 and
occupation of adjacent hydrophobic pocket are known to be critical
interleukin-6 (IL-6) and tumor necrosis factor
a (TNFa a
).10 As p38
activation is not involved in normal physiology, the downstream
effects of activation are thought to play pathophysiological roles
in inflammatory processes associated with diseases, such as rheu-
matoid arthritis,10–12 inflammatory bowel disease,13 congestive
for p38
within the p38
a
activity.26,27 Furthermore, a docking overlay of 2 and 3
a
ATP binding site (Fig. 3) suggests that appropriate
heart failure14 and psoriasis.15 Furthermore, since p38
a
activation
leads to cytokine expression, it is postulated that inhibition of
p38 can normalize this aberrant physiology and play a key role
in the treatment of inflammation-related diseases.
Driven primarily by the central role of p38 in several settings
substituents on the pyridine ring should reveal SAR similar to what
is known for the imidazole pyrimidine class of inhibitors.24
a
a
of inflammation, this enzyme has been an active target for drug
discovery efforts in the past decade.16–18 Numerous structural clas-
ses of p38a kinase inhibitors have been reported in the literature,
of which several have been evaluated in clinical trials (i.e., VX-745,
* Corresponding authors. Tel.: +11 86 22 66239656 (X.T.), tel.: +1 650 704 3051
(D.E.L.).
Figure 1. Structure and potency of indole carboxamide-based p38
a kinase inhib-
E-mail addresses: xuefei827@gmail.com (X. Tan), del345@gmail.com (D.E. Levy).
itor, (1).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.088

G. R. Luedtke et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2556–2559
2557
Table 1
p38a enzymatic potencies of N-pyridyl amides
R1
R2
p38 IC50
0.345
(lM, n = 3)
23
Figure 2. p38a screening hit (2) and imidazole pyrimidine p38a inhibitor (3).
Compd
4
5
6
7.8
1.22
5.08
1.11
0.671
7
8
9
Figure 3. Initial proposed binding modes of 2 (magenta) and Merck imidazole
pyrimidine p38 inhibitor 3 (blue) within the ATP binding pocket of p38 kinase.
a
a
10
0.589
0.408
11
12
H
0% @ 1 lM
the structures illustrated in Figure 3. Specifically, besides having
the same binding interactions as compound 2, the (S)- -methyl-
a
benzyl group of 4 should reside in the same region occupied by
the same moiety of compound 3.
To understand the role of the naphthyl region, diverse structural
alternatives to the naphthoyl group were studied. As shown in
Table 1, benzoyl and acetyl groups were well tolerated
Scheme 1. General procedure for the synthesis of N-pyridyl amides. Reagents and
conditions: (a) acid chloride, Et3N, DCM, 38–59%; (b) NaH, DMF then 4-fluorobenzyl
bromide, 27–60%; (c) amine, Pd(OAc)2, BINAP, Cs2CO3, dioxane, 110 °C, 20–74%.
Based on our modeling studies, a number of 2-amino substi-
tuted pyridine analogs were prepared according to Scheme 1. As
illustrated, acylation of 4-amino-2-chloro pyridine followed by
NaH deprotonation and treatment with 4-fluorobenzyl bromide
provided the desired amide. A Buchwald coupling was then used
to couple an amine to the pyridine 2-position giving the desired
products. Data for all analogs are shown in Table 1.
As shown in Table 1, incorporation of an amino (S)-
benzyl group on the pyridyl 2-position of compound 2 resulted
in a significant increase in potency (4; IC50 = 0.345 M). Further-
a-methyl-
l
more, the stereochemical configuration at the benzylic position
was found to be important as the opposite enantiomer 5, showed
a significant drop in potency. In addition, removal of the a-methyl,
removal of the benzyl, or replacement of the benzyl with a cyclo-
hexyl group (compounds 6, 7 and 8, respectively) significantly
reduced potency. However, incorporation of an isopropyl group,
9, maintained most of the activity associated with 4 illustrating
the importance of the
Regarding the p38
a
a
-methyl group.
binding mode of this series of structures,
compounds such as analog 4 are expected to bind similarly to
Figure 4. Additional analogs with associated p38a enzyme activities.

2558
G. R. Luedtke et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2556–2559
the hinge region. The naphthyl group is shown able to occupy
the adjacent p38
ficity. While the
a
hydrophobic pocket attributed to kinase speci-
a-methylbenzyl moiety sits in another hydropho-
bic pocket, a distal hydrogen bond interaction is seemingly formed
between the amide carbonyl oxygen and Lys-53. In fact, there is
precedence for such a binding mode involving Lys-53 and N-3 of
imidazole-based inhibitors.33 Furthermore, this binding mode can
be used to explain the potencies obtained for all analogs shown
in Table 1. The only exception is the activity of the acetyl analog
11 which is more appropriate explained by the originally proposed
binding mode. Finally, the new model suggests that the amide sub-
stituent could potentially be modified to pick up additional inter-
actions with neighboring amino acid such as Asp-112, Ser-154,
Asp-168 and Tyr-35.
Figure 5. Cis and trans rotational isomers of 17. Calculations show that the cis
isomer is 7.54 kcal/mol lower in energy than the trans isomer.30
In summary, a novel series of N-pyridyl amides was identified
as potent inhibitors of p38
between the initial hit 2 and known p38
a
kinase. Based on structural similarities
inhibitors, sub-micro-
a
molar activity was quickly achieved by applying SAR known for
imidazole pyrimidine-based inhibitors. However, the results of
these SAR studies, were inconsistent with the initial binding mode
proposed based on the structural similarities between the two ser-
ies. The newly proposed binding mode of amide 17 indicated that,
in this series, an energetically more favorable cis conformer may be
the actual bioactive conformation.
Figure 6. Cis and trans rotational isomers of N-acetyl-N-methylaniline. The cis
isomer is the dominant structure as demonstrated by X-ray crystallography.
(compounds 10 and 11, respectively). However, elimination of this
group altogether (compound 1228) resulted in a complete loss of
activity. Finally, proper positioning of the amide bond seemed
key to binding as, in 1329 and 14,29 relocation of this group relative
References and notes
to compounds 2 and 4 resulted in no inhibition at 1 lM (Fig. 4).
Additional support for the importance of the amide is found in
the decrease in activity noted when alternative functional groups
were used (Fig. 4, compounds 1528 and 1628).
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Figure 7. Docking overlay of 17-cis conformer with Merck imidazole pyrimidine
compound 3 within the ATP binding pocket of p38a kinase.

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2559
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