SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity and metabolic stability

Article abstract of DOI:10.1016/j.bmcl.2010.07.036

SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1′ pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.

Full text of DOI:10.1016/j.bmcl.2010.07.036

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5039–5043
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity
and metabolic stability
a,
a
b
a
Donghong Amy Gao a, , Zhaoming Xiong , Alexander Heim-Riether , Laura Amodeo , E. Michael August ,
Xianhua Cao c, Leonard Ciccarelli c, Brandon K. Collins a, Kyle Harrington c, Kathleen Haverty a,
Melissa Hill-Drzewi a, Xiang Li b, Shuang Liang a, Steluta Mariana Margarit a, Neil Moss a,
Nelamangala Nagaraja c, John Proudfoot a, Rene Roman c, Sabine Schlyer a, Lana Smith Keenan a,
Steven Taylor a, Bernd Wellenzohn d, Dieter Wiedenmayer e, Jun Li b, Neil A. Farrow a
*
*
a Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Rd, Ridgefield, CT 06877, USA
b Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Rd, Ridgefield, CT 06877, USA
c Department of Drug Discovery and Support, Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Rd, Ridgefield, CT 06877, USA
d Department of Lead Discovery, Boehringer Ingelheim Pharma GmbH and Co. KG. Birkendorfer Strasse 65, D-88397 Biberach an der Riss, Germany
e Department of Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH and Co. KG. Birkendorfer Strasse 65, D-88397 Biberach an der Riss, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13
inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S10 pocket.
Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower
in vivo clearance for the preferred compound.
Received 18 June 2010
Revised 7 July 2010
Accepted 9 July 2010
Available online 15 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
MMP-13
Non-Zn-chelating inhibitor
SAR
Selectivity
Metabolic stability
The matrix metalloproteinases (MMPs), comprised of collagen-
ases, stromelysins, gelatinases, and membrane-type MMPs, are a
family of more than 27 zinc- and calcium-containing enzymes that
play a critical role in degradation of extracellular matrixes (ECM)
and in tissue remodeling.1 Of the collagenase family (MMP-13,
MMP-1 and MMP-8), MMP-13 exhibits the most efficient cleavage
of type II collagen.2 Inhibition of MMP-13 reduces cartilage degra-
dation associated with the progression of rheumatoid arthritis and
osteoarthritis in animal models.3 Consequently, MMP-13 has
become an attractive therapeutic target for treatment of these
diseases. Clinical data indicates that broad-spectrum MMP inhibi-
tors exhibit a dose-limiting toxicity referred to as musculoskeletal
syndrome (MSS) that involves painful joint stiffness and inflamma-
tion.4 It is hypothesized that MSS might be caused by inhibition of
normal extracellular matrix turnover due to inhibition of MMPs
other than MMP-13.5 However, this is yet to be proven, and it
remains unclear which MMP isoforms may be involved6 and to
what extent they individually contribute to MSS. Therefore, selec-
tive MMP-13 inhibitors might avoid MSS while providing thera-
peutic benefits. Thus, the research in this field has shifted from
broad-spectrum MMP inhibitors to highly selective MMP-13 inhib-
itors.7–9
We recently reported10 a new class of potent and selective
MMP-13 inhibitors with a unique binding mode in which the
inhibitors bind in the active site but do not interact with the cata-
lytic zinc. That work started with compound 1 (Fig. 1). Potency for
MMP-13 and selectivity were improved mainly through modifying
the interactions with the MMP S10 pocket by replacing the chlorine
with pyrazole ether (compound 2). Compound 2 shows good
MMP-13 potency (4 nM) and selectivity against most MMPs tested.
However, its selectivity against MMP-3 and -10 is modest (46- and
24-fold, respectively). Compound 2 also has poor metabolic stabil-
ity (HLM: 90% QH). Here we report our continued efforts to improve
the selectivity against both MMP-3 and -10 and the metabolic
stability of this class of MMP-13 inhibitors.
* Corresponding authors. Tel.: +1 203 798 4854; fax: +1 203 791 6072 (Z.X.); tel.:
+1 203 791 6638; fax: +1 203 791 6072 (D.A.G.).
E-mail addresses: amy.gao@boehringer-ingelheim.com (D.A. Gao), zhaoming.
xiong@boehringer-ingelheim.com (Z. Xiong).
To further improve selectivity over MMP-3 and -10 for this class
of inhibitors, we investigated alternative ways of interacting with
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.036

5040
D. A. Gao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5039–5043
Our previous report:[10]
O
O
NH
NH
HN
Cl
HN
O
O
N
O
N
O
N
O
1
2
MMP-13 IC50: 430 nM
MMP-13 IC50: 4 nM
selectivity: MMP-3: 46-fold; MMP-10: 24-fold
This work:
N
O
O
Ar
N
O
O
HN
NH
R'
HN
NH
3
4
HN
HN
O
O
O
O
3
4
MMP-13 IC50: 100 nM
selectivity: MMP-3: 150-fold; MMP-10: 23-fold
best compound: MMP-13 IC50: 5 nM
selectivity: MMP-3: 600-fold; MMP-10: 200-fold
Figure 1. Two approaches to gain potency and selectivity.
the S10 pocket. The starting point of this optimization was the result
of a hybridization of compound 1 with another series of MMP-13
inhibitors11 based on an overlay of their crystal structures. This
resulted in compound 3. Although compound 3 is less potent
than compound 2, the selectivity profile is equivalent to 2. We
considered compound 3 a reasonable starting point for further
exploration. We reasoned that aryl groups appended at the C-3
position of phenyl ring through a methyl amide linkage (as shown
in general structure 4) must occupy the MMP S10 pockets some-
what differently than the analogous functionality in compound 2.
Presumably this would offer different opportunities to improve
the selectivity against MMP-3 and -10. To test this hypothesis,
SAR studies started with replacing the imidazopyridyl group of 3
with other aromatic derivatives (Table 1).
five- or six - membered aromatics are not beneficial for MMP-13
potency (10 vs 8; 14 vs 13; 23 and 24 vs 17). Appending the same
arylcarboxamide groups to the C-4 position, rather than the C-3
position of the phenyl template resulted in much weaker inhibitors
(data not shown).
Investigating different aryl groups that presumably bind in
the S10 pocket resulted in compounds with good overall MMP
selectivity and good MMP-13 potency. However, the best com-
pounds (22 and 27) were metabolized rapidly in vitro (HLM:
81% and 66% QH for 22 and 27, respectively) (Table 2). We pos-
tulated that the high lipophilicity of these compounds contrib-
uted to the high rate of metabolism. The calculated log P
(c log P) value is 4.98 for 22 and 4.13 for 27. One way we
investigated the impact of reducing lipophilicity on rates of
metabolism concentrated on modifying the cyclohexyl group.
Since the cyclohexyl group binds in the S20 pocket and is
partially solvent-exposed as shown by the co-crystal structure
of MMP-13 and compound 1,10 we thought it would be possible
to modify this group without affecting potency and selectivity by
reducing the size and/or adding an oxygen. These modifications
lowered the c log P by up to 2.4 units. For the compounds 28–31
with 6-trifluoromethylpyridyl group, these modifications did not
have much effect on the metabolic stability. For the pyrimidine
analogs 32–35, the smaller groups (isopropyl or cyclopropyl) had
no effect on the metabolic stability (32 and 33 vs 27). However,
the more polar groups improved the metabolic stability to less
than 25% QH (34 and 35 vs 27). These structural changes have
no, or minor effects on MMP-13 potency: ꢀ3 fold better for the
4-tetrahydropyranyl group (30 vs 22; 34 vs 27), and three to five
fold less potent for cyclopropyl group (29 vs 22; 33 vs 27). In
general the changes decreased the MMP-2, -3 and -10 selectivities
to some extent. However, the best compound (35) from these
modifications has a good balance of potency, selectivity and meta-
The compounds reported herein (Table 1 and 2) were synthe-
sized in a straightforward manner as shown in Scheme 1.
The imidazopyridyl group of 3 is clearly important since replac-
ing it with a methyl group significantly lowers both potency and
selectivity (compound 5). Simple methyl-substituted imidazopyri-
dines (6 and 7) showed no impact on either potency or selectivity.
Due to the relatively high molecular weight (513 dalton) of 3, we
concentrated primarily on replacing the imidazopyridyl group
with smaller aromatic rings. We were pleased to find that a
number of five- and six - membered aromatic groups not only
improved the potency to the same level of compound 2, but also
improved the selectivity over MMP-3 and -10 significantly. Among
the fivemembered aromatics we examined, the most potent com-
pounds (9, 13, and 16) appear to have structural features combin-
ing an H-bond acceptor at 2-position (next to the carbon with the
carboxamide group, see structures in Table 1) and a methyl group
at 3-position (next to the H-bond acceptors). However, their selec-
tivity compared to compound 3 remained the same or became
worse. Among the six - membered aromatics (pyridines and pyrim-
idines), an H-bond acceptor (N) at the 2-position also appeared to
be beneficial for the MMP-13 potency (19 vs 20; 25 vs 26). Substi-
tutions (Me, Cl or CF3 groups) at the 3-position for compounds with
an H-bond acceptor at 2- position do not affect MMP-13 potency
(21 and 22 vs 17; 26 and 27 vs 20). However, the bulkier trifluoro-
methyl group at 3-position (compounds 22 and 27) significantly
improves selectivity over MMP-3 and -10 to almost 400-fold. Small
substitutions (mostly methyl group) at other positions of either
bolic stability. It also has good aqueous solubility (>50
both pH 4.5 and 7.4.
lg/mL) at
To establish whether the in vitro improvement of metabolic sta-
bility of 35 translated into in vivo clearance, the intravenous phar-
macokinetics of compounds 35 and 33 were evaluated in male SD
rats at a 1 mg/kg dose (Table 3).14 The in vivo clearance of the two
compounds is comparable to their in vitro clearance, with com-
pound 35 having the lower clearance.

D. A. Gao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5039–5043
5041
Table 1
SAR to improve potency and selectivity13
O
R
O
HN
NH
HN
O
O
R
Compound
MMP-13 IC50 [nM]
MMP-2
MMP-3
MMP-8
MMP-10
Fold selectivity for MMP-13
N
N
3
5
100
>190
5
150
3
>190
>7
23
N
N
3300
0.5
6
7
8
9
110
140
75
>45
>37
>45
>37
15
>45
>37
29
32
6
N
N
3
3
2
O
>270
490
>270
>1900
1
2
O
11
34
16
1
O
10
11
12
180
330
310
>110
>61
>110
9
>110
>61
17
8
O
N
>64
>64
>64
9
N
2
3
N N
13
24
>430
33
>820
14
1
N N
14
15
72
>280
>150
51
20
>280
>150
19
13
N
N
140
2
N
3
S
16
8
310
Not tested
1800
7
1
3
2
N
17
18
8
>2400
>480
200
>2400
48
65
7
1
N
42
Not tested
N
N
19
20
31
10
310
290
Not tested
Not tested
>660
4
9
N
>2000
N
F
21
22
4
9
>4900
>2300
240
>4900
>2300
87
F
F
3
2
N
>2300
>2300
1
N
23
24
100
29
>200
>170
85
>200
>170
31
45
N
>170
Cl
Cl
25
26
27
3
370
590
Not tested
Not tested
>740
10
N
N
N
>7100
27
(continued on next page)

5042
D. A. Gao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5039–5043
Table 1 (continued)
R
Compound
MMP-13 IC50 [nM]
MMP-2
>2800
MMP-3
MMP-8
>2800
MMP-10
370
Fold selectivity for MMP-13
F
F
F
3
2
27
7
>2800
N
N
1
Table 2
SAR to improve metabolic stability13
O
R
O
HN
NH
R'
HN
O
O
R
Compound
R0
MMP-13 IC50 [nM]
MMP-2
MMP-3
MMP-8
MMP-10
>2300
HLM [%QH]
c log P
Fold selectivity for MMP-13
22
9
>2300
>2300
>2300
81
4.98
28
29
6
>3600
>700
1000
>700
>3600
>700
260
400
88
60
3.79
3.31
F
F
F
28
N
30
31
27
2
25
7
1500
>770
330
>400
7100
>810
>2800
130
440
370
83
62
66
2.58
2.60
4.13
O
OH
>2800
>2800
32
33
9
850
580
200
540
>2100
>560
50
70
69
2.94
2.45
F
F
F
36
170
N
N
34
35
2
5
640
250
600
>11000
>3900
100
200
24
14
1.73
1.74
O
1100
OH
Table 3
Pharmacokinetic data (iv) of 33 and 35a
O
O
O
b
H
N
a
H
N
O
H2N
O
N
H
N
H
OH
O
R'
R'
O
R'
Compound
HLM (%QH)
CL (%QH)
Vss (L/kg)
T1/2 (h)
33
35
69
14
47
26
1.2
0.9
0.7
0.95
O
c
d
NH
R'
a
The compounds were dosed in 70% PEG400 aqueous solution.
HN
OH
O
OH
B
O
O
O
Br
O
Br
O
N
H
OH
O
aryl groups with methyl amide linkage from C-3 position of phenyl
template. Further optimization of metabolic stability was achieved
by reducing lipophilicity to provide 35. Overall, compound 35
exhibits good potency, selectivity, metabolic stability and aqueous
solubility. The improved in vitro metabolic stability of compound
35 also translated into low clearance in vivo.
O
O
R
e, c
O
O
NH
HN
NH
HN
HN
R'
HN
RCOOH
R'
O
O
O
O
Acknowledgments
Scheme 1. Reagents and conditions: (a) MeNH2ꢁHCl, TBTU, DIEA, DMF, rt; (b) TFA,
DCM; (c) HATU, DIEA, DMF; (d) PdCl2{PtBu2(p-NMe2-Ph)}2,12, Na2CO3 (2 M), DMF,
microwave 100 °C; (e) 4 N HCl in dioxane, MeOH.
The authors wish to thank Drs Jeremy Levin, Dan Marshall and
Erick Young for their careful review of the manuscript.
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selectivity of a previously reported class of MMP-13 inhibitors pos-
sessing a unique binding mode. The improvements in potency and
selectivity, especially for MMP-3 and -10, were achieved through
the modification of interactions with the S10 pocket by appending
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13. Compounds were also tested in MMP-1, -7, -9, -12, -14 assays, and their IC50s
6. It was initially believed that inhibition of MMP-1 or MMP-14 was the cause of
MSS. Studies on MMP-14 KO mice support MMP-14 being a strong candidate
for MSS: see Ref. 4b. However, clinical data with CP-544439, a non-selective
hydroxamic acid-based MMP-13 inhibitor showed MSS side effects even
though it is inactive against MMP-1. See: Reiter, L. A.; Robinson, R. P.; McClure,
are greater than the top concentration (20
see Ref. 10.
14. For comparison, compound 27 was also selected for an intravenous
lM). For detailed assay conditions,
pharmacokinectics study. But the study failed due to its poor solubility
(0.1 lg/mL).