Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis

Article abstract of DOI:10.1016/j.bmcl.2011.04.028

A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.

Full text of DOI:10.1016/j.bmcl.2011.04.028

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3301–3306
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4
(aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment
of osteoarthritis
Chris De Savi a,b, , Andrew Pape a, Yvonne Sawyer a, David Milne a, Chris Davies a,b, John G. Cumming a,
⇑
Attilla Ting a,b, Scott Lamont a,b, Peter D. Smith a,b, Jonathon Tart a,b, Ken Page a, Peter Moore a
a Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
b Oncology Innovative Medicines, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been dis-
covered through modification of the complex P1 group present in historical inhibitors 1. This structural
change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent
cross-MMP selectivity profiles. Investigation of structure–activity and structure–property relationships in
the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the
identification of a pre-clinical candidate with excellent bioavailability across three species and predicting
once daily dosing kinetics.
Received 12 March 2011
Revised 2 April 2011
Accepted 6 April 2011
Available online 13 April 2011
Keywords:
ADAM-TS4
ADAM-TS5
Ó 2011 Elsevier Ltd. All rights reserved.
Aggrecanase
Reverse hydroxamate
Osteoarthritis
Osteoarthritis (OA) remains the most common form of arthritis
and is the leading cause of disability in elderly adults both in the
United States1 and the United Kingdom.2 Treatment options are
limited to steroidal and non-steroidal anti-inflammatory drugs
(NSAIDS)3 and although providing symptomatic relief for pain
and inflammation in arthritis they have failed to modify the pro-
gression of the disease.4,5 The goal of OA treatment is to control
symptoms, prevent disease progression, minimize disability and
improve the quality of life. It is believed that inhibition of aggre-
canase has the potential to prevent further damage to the joint
and/or slow disease progression by stopping cartilage catabolism.
‘Aggrecanase-1’ (ADAM-TS4)6 and ‘Aggrecanase-2’ (ADAM-TS5)7
have been identified as the most likely members of the ADAMTS
(a disintegrin and metalloproteinase with thrombospondin) family
to be responsible for cartilage aggrecan degradation and remain
attractive drug targets for intervention in OA.8,9 ADAM-TS5 is
responsible for disease progression in a surgically-induced model
of OA in mice10 nonetheless the relative individual contributions
of ADAM-TS4 and ADAM-TS5 proteases to cartilage pathology in
human disease is not fully understood.11 We have previously re-
ported the discovery of a potent series of chiral N-hydroxyforma-
mide ADAM-TS4 inhibitors with excellent selectivity versus all
tested matrix metalloproteinases which led to the identification
of an advanced pre-clinical candidate 1.12 The strategy of the sub-
sequent medicinal chemistry programme was to explore SAR for
both ADAM-TS4 and ADAM-TS5.
We now wish to report further advances in improving DMPK
properties whilst maintaining cross-MMP selectivity and signifi-
cantly simplifying the core structure associated with 1 via modifi-
cations to the P1 group, ultimately leading to simple achiral
homologues 2.
P1
R
N
O
F
O
S
N
O
S
O
N
N
N
O
N
O
OH
N
OH
O
P1'
O
1
2
Compound 1 was shown to be a potent inhibitor of both ADAM-
TS4 and ADAM-TS5, >1000ꢀ selective versus all tested metallopro-
teinases (with respect to ADAM-TS4). It possessed only moderate
oral bioavailability in mouse and dog and poor bioavailability in
rat. Although a stereoselective synthesis of 1 was achieved, the
synthesis consisted of 17 discrete synthetic transformations from
⇑
Corresponding author.
E-mail address: chris.desavi2@astrazeneca.com (C. De Savi).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.028

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C. De Savi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3301–3306
commercially available starting materials. The optimised medici-
nal chemistry route was used to deliver >320 g of drug substance
for early rat and dog toxicology profiling but developing a cost-effi-
cient route suitable for multi-kilogram production was a signifi-
cant challenge.
The primary goal therefore was to design a molecule that
maintained all the desirable properties associated with 1 (viz.
ADAM-TS4 potency and excellent cross-MMP selectivity) but with
significant reductions to synthetic complexity and associated cost-
of-goods. In addition, a molecule with higher bioavailability across
three pre-clinical species was highly desirable in order to increase
confidence in achieving good oral exposure in humans.
corresponding alkene 9 as a mixture of E/Z isomers in high yield
(70–80%). Typically, the crude alkenes were subjected to hydroge-
nation to form the Peterson precursor sulfonamide 10 in 95–100%
yields. The Peterson reaction of 10 with tetrahydropyran-4-one
proceeded smoothly to deliver alkene 11 which was subjected to
reaction with hydroxylamine to deliver compound 12. Subjection
of 12 to acylation conditions described by us previously12 gener-
ated the final reverse hydroxamates 13 in moderate to good yields.
This synthesis of achiral reverse hydroxamates consists of only
nine discrete steps (vs 17 steps for synthesis of chiral compound
1) and results in high overall yields of up to 44% of final
compounds.
Previously, we showed that the addition of a methyl group adja-
cent to the N-hydroxyformamide to produce a quaternary reverse
hydroxamate significantly reduced Cyp 3A4 activity consistently
across multiple series (ethyl piperidine and piperazines).12 This
interesting finding prompted us to explore other sterically encum-
bered reversed hydroxamates to further understand Cyp 3A4 SAR
(Fig. 1). By focusing on molecules with symmetry at the reverse
hydroxamate the problem of controlling chirality is removed. The
fully substituted gem-dimethyl compound 4, is not a potent Cyp
3A4 inhibitor unlike its di-substituted analogue, racemate 3. On
the other hand, the cyclobutyl analog 5 is presumably due to the
angle strain of 60° between carbon atoms associated with the
cyclobutane providing less steric hindrance. The cyclic analogues,
piperazine 6 and tetrahydropyran 7 are also free of Cyp 3A4
inhibition.
Due to both the clean Cyp3A4 profile and the good ADAM-TS4
potency associated with tetrahydropyran 7, we chose to fix the tet-
rahydropyran P1 group and explore P10 SAR. A generalized conver-
gent scheme for the synthesis of analogues 13 is shown in Scheme
1.
The triphenylphosphonium halides 8 were sourced commer-
cially or could be accessed from the reaction of a commercial aryl
or heteroaryl halide with PPh3 using standard conditions.13 The
ylides were formed in the presence of KOtBu and reacted with
1-(methylsulfonyl)piperidine-4-carbaldehyde14 to generate the
Analogues 13a–n were tested for inhibition of both ADAM-TS4
and ADAM-TS5 and a selection of MMPs to elucidate aggrecanase
potency and selectivity. The majority of P10 groups in this SAR
exploration had previously been used in the fluoro-pyrimidine
piperidine series 1,12 enabling a Matched Molecular Pair Analysis
to be performed.15 Generally, the ADAM-TS4 potency of the pyran
P1 compounds was reduced by 1 to 1.5 log units compared to their
fluoropyrimidine P1 matched pair analogues (Fig. 2, mean differ-
ence in ADAM-TS4 pIC50 = ꢁ1.6, standard error of mean = 0.24,
N = 14 pairs), however the compounds maintained good to excel-
lent selectivity profiles versus the MMPs tested (Table 1). The most
selective analogues were compounds 13b, 13l and 13n achieving
up to >7000-fold selectivities across all MMPs tested.
Substituting the pendant phenyl ring in both the ortho- and
para-positions is important to obtain optimum selectivity for
MMP13 and MMP14—the simple phenyl homologue 13e has mod-
erate ADAM-TS4, MMP13 and MMP14 potency. The addition of an
ortho-methyl to the aryl group (13f) significantly improves ADAM-
TS4 potency and introduces moderate selectivity over MMP13. The
addition of a further substituent to the para-position (13a and 13c,
chloro and sulfone groups respectively) significantly improves
selectivity over both MMP13 and MMP14, whilst maintaining very
good ADAM-TS4 activity. Generally, the pyridyl analogues (13d,
13g, 13h, 13i) were less potent than analogues containing substi-
tuted aryl P10 groups. Moving the pyridyl nitrogen from the 3 to
O
S
O
S
O
S
O
S
O
S
O
N
F
F
N
N
N
N
F
N
N
H
F
N
F
N
N
N
O
O
O
O
N
N
O
N
OH
N
OH
N
OH
OH
OH
7
O
O
4
3
6
5
O
O
O
Cyp 3A4 IC50
ADAM-TS4 IC50: 530 nM
:
>10 µM
Cyp 3A4 IC50: >10 µM
Cyp 3A4 IC50
:
>10 µM
Cyp 3A4 IC50
ADAM-TS4 IC50: 91 nM
MMP-13 IC50
81%a
MMP-14 IC50: nt
MMP-1 IC50: nt
: 1.9 µM
Cyp 3A4 IC50
ADAM-TS4 IC50: nt
:
1 µM
ADAM-TS4 IC50: 21 nM
MMP-13 IC50: 97%a
MMP-14 IC50: nt
ADAM-TS4 IC50: 92 nM
MMP-13 IC50: 1400 nM
MMP-14 IC50: 1400 nM
MMP-1 IC50: >10 µM
MMP-13 IC50
MMP-14 IC50
MMP-1 IC50
:
:
:
570 nM
2900 nM
>6700 nM
:
MMP-13 IC50
MMP-14 IC50
:
:
154 nM
226 nM
MMP-1 IC50: nt
MMP-1 IC50: >10 µM
Figure 1. Cyp 3A4, ADAM-TS4 and MMP inhibitory activity for di-substituted reverse hydroxamates; nt = not tested; apercent inhibition of enzyme activity at 15
lM.
O
S
O
H
O
O
O
N
R
H2
O
S
O
S
R
O
S
R
R
O
N
N
PPh3Cl
N
LiHMDS, TMSCl,
THF, -78°C, 80%
Pd/C
KOtBu, EtOAc, slurry
70-80%
O
O
O
95-100%
8
10
9
11
NH2OH
n-PrOH
85%
Ac2O (20 mol eq.)
HCOOH (40 mol eq.)
O
O
R
O
S
O
R
N
S
N
O
N
66-77%
O
OH
HN
13
OH
O
12
Scheme 1. General route to tetrahydropyrans 13.

C. De Savi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3301–3306
3303
Figure 2. Matched pair analysis of ADAM-TS4 potency (pIC50) versus sub-core
structure (F-pyrimidine core vs achiral tetrahydropyran core); lines linking
matched R group pairs.
4 position (13k vs 13l) resulted in a significant increase in ADAM-
TS4 potency and an excellent selectivity profile, suggesting this
was an optimal position for the pyridyl variants. Five-membered
heterocycles 13j and 13n also showed good to moderate potency
versus ADAM-TS4 with good to excellent selectivity profiles com-
pared to multiple MMPs (this was also seen for matched pair
compounds in the historical fluoropyrimidine series). The major-
ity of compounds tested were only moderate inhibitors of ADAM-
TS5, nonetheless 2-methylphenyl derivative 13f was potent ver-
sus ADAM-TS5 (IC50 = 31 nM) but suffered from a poorer cross-
MMP selectivity profile. Furthermore, compounds 13b and 13l
were potent ADAM-TS4 inhibitors showing enhanced selectivity
over ADAM-TS5 (700- and 200-fold selectivity ratios, respec-
tively). A comprehensive exploration of novel cyclic P1 groups
was next undertaken to probe the S1 pocket and its impact on
ADAM-TS4 and -TS5 selectivity (Table 2). From previous ADAM-
TS1 protein X-ray crystal structures and modelling to ADAM-
TS4 it was known there are polar residues around this area for
potential interactions, and also extending this group would
eventually access a solvent channel so this could also be an ideal
physical property modifying handle. The P10 group was fixed as
the 3,5-dimethylisoxazolyl moiety (a potent and selective group)
and P1 changes primarily focused on symmetrical cyclic groups
that were predicted not to introduce major clashes and be
complementary with the S1 pocket of ADAM-TS1 from modelling,
and could be synthesised from readily available ketone precur-
sors.17 As predicted all compounds (14a–14l) tested were quite
selective compared to other MMPs tested, presumably due to
the selective isoxazole P10 group common to all compounds.
Modest increases in ADAM-TS4 potency were achieved in ana-
logues 14a, 14e and 14i (cf. lead compound 13n). However, the
more lipophilic cyclohexyl derivative (14l) offered no particular
advantages in potency or selectivity. Four-, five- and seven-
membered variants (14c, 14k and 14d) were all less potent in
ADAM-TS4.
Compound 14e showed potent ADAM-TS4 inhibition, good
ADAM-TS5 potency and excellent selectivity albeit it suffered
from high in vitro metabolic turnover. We tried to optimize this
desirable TS4/TS5 mixed profile by synthesising a range of com-
pounds with P10 groups, which had previously shown good

3304
C. De Savi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3301–3306
Table 2
ADAM-TS4/5 and cross-MMP inhibitory activity of P1 changes to compound 13n
O
N
O
N
O
N
S
O
O
R
c
d
Compds
14a
R
ADAM-TS4
ADAM-TS5
MMP-2
MMP-13
IC50, nM
MMP-14
IC50, nM
MMP-9
IC50, nM
Hu Clint
L/min/mg)
Rat Clint
L/min/106 cells)
Cyp 3A4
IC50
a
a
b
IC50
,
nM
IC50
,
nM
IC50
,
nM
(l
(
l
lM
N
11
480
>10,000
>10,000
>10,000
4600
>10,000
>10,000
>10,000
>10,000
31
O
N
14b
29
310
6.5
N
S
O
O
14c
14d
51
48
1500
1500
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
3.3
59
N
14e
10
270
>10,000
>10,000
>10,000
>10,000
65
92
>10
O
14f
14g
14h
20
16
24
410
270
820
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
13
4.9
<2
126
30
>10
>10
F
F
S
O
O
N
O
14i
14j
9.7
19
250
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
12
<2
47
<2
>10
>10
O
N
1200
14k
14l
52
20
1900
850
>10,000
>10,000
>10,000
>4100
>10,000
>7500
>10,000
>10,000
a–d
See footnotes from Table 1.
ADAM-TS5 potency (see 13a, 13f and 13m) and the P1 group from
14e (Table 3). The majority of these P10 groups have an ortho-
methyl group with/without a halogen in the para-position. These
compounds represent potential probe compounds to test the
hypothesis that a dual aggrecanase inhibitor void of collagenase
activity is beneficial for treating OA.
The achiral reverse hydroxamate compound class was relatively
stable in both human microsomes and rat hepatocytes and a se-
lected number of examples (13j, 13l, 13m and 13n) were dosed
in vivo to rat (see Table 1). These selected compounds all showed
moderate clearance with Vdss generally within the range of 2–3
L/kg leading to good iv half-lives. Isoxazole 13n showed particu-
larly good t1/2 (8.9 h) in rat which warranted both oral profiling
and further investigation in other species.
tively) coupled with excellent oral absorption in all pre-clinical
species dosed (F% 45–54; Fabs 0.62–1.0). A small amount of excre-
tion of parent compound was observed in rat and dog urine and no
parent compound was detected in rat bile. Clint data generated in
hepatic microsomes and hepatocytes from both species predicted
in vivo clearance well (within twofold of observed data). Taken to-
gether, these observations suggested that elimination of this com-
pound was predominantly via hepatic metabolism. Furthermore,
compound 13n showed no evidence of competitive or time depen-
dent CYP inhibition or induction of major inducible CYPs and no
evidence for the presence of reactive products. Assuming that free
exposure must exceed fivefold ADAM-TS4 IC50 over the entire dos-
ing period, human doses of 13n required for efficacy were pre-
dicted to be low (7–126 mg/day b.i.d.), a result of good predicted
bioavailability (68%), low human clearance (3.5 mL/min/kg) and
moderate volume (5.2–10.6 L/kg), resulting in an elimination
half-life entirely consistent with either once or twice daily dosing
(range 17–60 h).19
Compound 13n showed further good pharmacokinetic proper-
ties in both mouse and dog (Table 4) showing low to moderate
clearance with high volumes and relatively prolonged elimination
half-lives (t1/2 = 2.6, 8.9 and 19.1 h in mouse, rat and dog, respec-

C. De Savi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3301–3306
3305
Table 3
ADAM-TS4 and ADAM-TS5 inhibitory activities of selected achiral analogues of 14e
O
O
S
N
R
N
O
N
HO
O
Compds
R
ADAM-TS4
IC50, nM
ADAM-TS5
IC50, nM
15a
15b
15c
15d
15e
4-Fluoro-2-methylphenyl
2-Methylphenyl
4-Chloro-2-methylphenyl
4-Fluoro-2-(trifluoromethyl)phenyl
2-Methyl-4-(trifluoromethyl)
1.9
4.1
1.2
8.7
1.2
11
13
20
61
79
Figure 3. Human cartilage was stimulated with interleukin-1, oncostatin-M and
plasminogen for 21 days in the absence or presence of 10 lM compound 1.
A detailed comparison of the profile of compound 13n with the
more complex chiral compound 1 was performed Although com-
pound 13n is approximately 40-fold less potent in ADAM-TS4 it
maintains an excellent selectivity profile vs all MMPs tested, has
low in vitro clearance across three species, has far superior free lev-
els in all three pre-clinical species (fu = >0.5), and displays superior
bioavailability across three clinical species (mouse, rat and dog)
ultimately leading to predicted once daily human dosing profiles.
The significantly improved absorption profiles of achiral com-
pound 13n is intriguing and we hypothesise that this could be
due to a combination of overall molecule properties of compound
13n compared to compound 1: (1) molecular weight (MWt) is sig-
nificantly lower20 (MWt 429 vs 511), (2) one less aromatic ring,21
(3) one less rotatable bond, (4) higher fraction of sp3 C atoms22
(0.70 vs 0.84, compounds 13n and 1, respectively). Furthermore,
due to the removal of the two chiral centres in compound 1 and
the improved yields in key synthetic steps, compound 13n is also
significantly cheaper to synthesise on multi-kg scale. Although
both compounds 1 and 13n represented excellent pre-clinical can-
didates in terms of their pharmacokinetic, enzyme selectivity and
early in vitro safety profiles, it was important to demonstrate their
ability to inhibit breakdown of aggrecan and collagen in disease-
relevant tissues.
of aggrecanases results in longer-term protection of the collagen
network.23
The production and release of the aggrecanase specific neo-epi-
topes, NITEGE and AGRSVIL, was studied in ex vivo cartilage ex-
plant cultures. A good correlation between NITEGE and ARGSVIL
readouts has been demonstrated in human articular cartilage with
compound 1 (data not shown). Compound 13n was shown to inhi-
bit both the spontaneous aggrecan degradation in late stage dis-
eased OA cartilage (IC50 for release of ARGSVIL neo-epitope: 150–
350 nM) and IL-1 stimulated human OA cartilage (IC50 for release
of ARGSVIL neo-epitope: 120–218 nM).
Compound 1 inhibited NITEGE neo-epitope release in IL-1 stim-
ulated human articular cartilage (IC50 = 243nM)12 and was also
used to demonstrated protection of the collagen network. This
was determined by reduction of type II collagen C terminal telo-
peptide (CTXII)24 release in the presence of compound 1 at day
14 and 21 post stimulation with IL-1, oncostatin-M and plasmino-
gen (Fig. 3). These data support the hypothesis that protection of
cartilage aggrecan may ultimately lead to preservation of the inter-
twined collagen network by sterically hindering the action of
collagenases.23
Ex vivo cartilage explant studies using selective aggrecanase
and MMP inhibitors have demonstrated that selective inhibition
Compound 1 was also studied in the Dunkin Hartley guinea pig
model of spontaneous osteoarthritis.25 In these studies compound
Table 4
Profiles of advanced compounds 1 and 13n
Parameter
1
13n
a
ADAM-TS4/TS5 IC50
0.7/23 nM
>5000ꢀ
1.6
26/860 nM
>5000ꢀ
0.9
a
Fold selectivity MMP1,2,9,13,14 IC50
Log D
Solubility (
l
M)b
150
>1000
Hu/rat/dog %free (%free)
11/22/25
29.4/<2
>50 (3/3)
3.1/<2
d
Hu Micsc/Heps Clint
e
Cyp Inhib pIC50
hERG IC50
>10
65
l
M (5/5)
>10
l
M (5/5)
18
lM
>100
lM
Caco-2 (@10
l
M)f
5.3 ꢀ 10ꢁ6 AB/10.9 ꢀ 10ꢁ6 BA
16.8 mL/min/kg/5.4 h/7.2 L/kg
11 mL/min/kg/11 h/7.4 L/kg
20.7 mL/min/kg/11.3 h/9.2 L/kg
34/1/20
8.3 ꢀ 10ꢁ6 AB/ꢁ
Mouse PK Cl/t1/2/Vdss
30 mL/min/kg/2.6 h/2.5 L/kg
24 mL/min/kg/8.9 h/3.0 L/kg
13 mL/min/kg/19.1 h/10.9 L/kg
54/45/52
Rat PKg Cl/t1/2/Vdss
Dog PKh Cl/t1/2/Vdss
Mouse/rat/dog F%
Human pDTM dose (mg/day)
14 b.i.d
7–126 b.i.d; 63 qd
a
For general assay procedures see Ref. 12. IC50’s were derived from at least six measurements whose standard errors were normally <5% in a given assay. Assay to assay
variability was within twofold based on the results of a standard compound.
b
c
d
e
f
Thermodynamic solubility (lM) in 0.1 M phosphate buffer pH 7.4 at constant temperature (25 °C) for 24 h.
Human microsome metabolism intrinsic clearance Clint
Human hepatocyte metabolism intrinsic clearance Clint
(
l
L/min/mg). Clint reported is mean of eight separate experiments.
(
l
L/min/106 cells). Clint reported is mean of six separate experiments.
Inhibition of cytochrome P450 isoforms: 1A2, 2C9, 2C19, 2D6 and 3A4. NA = not active.
Apparent permeability (Papp cm/s ꢀ 10ꢁ6) in human cancer colon cells at 10
lM/pH7.4. AB—apical to basolateral direction; BA—basolateral to apical direction (efflux).
Compounds dosed at 2 mg/kg iv, n = 2 animals and 3–10 mg/kg po, n = 4 animals.
g
h
Compounds dosed at 1 mg/kg iv, n = 4 animals and 1 mg/kg po, n = 4 animals.

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Figure 4. Compound 1 was administered for 7 days by sub-cutaneous mini-pump
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In summary, we have discovered a novel series of achiral N-
hydroxyformamide inhibitors of ADAM-TS4 and ADAM-TS5 with
improved pharmacokinetic properties and more cost-efficient
large scale synthesis compared to our previous chiral series.
Emerging SAR has led to ADAM-TS4 selective and equipotent
ADAM-TS4/TS5 potent compounds. Compound 13n is a potent
and highly selective aggrecanase inhibitor with pharmacokinetic
properties predicted to be consistent with once daily dosing in hu-
mans, and thus has the potential to test the hypothesis that inhibi-
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Preliminary testing of compound 1 supports the hypothesis that
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ADAM-TS1 structure (PDB ID = 3Q2H) and overlaid with compound
1 in
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References and notes
1. Helmick, C. G.; Felson, D. T.; Lawrence, R. C.; Gabriel, S.; Hirsch, R.; Kent Kwoh,
C.; Liang, M. H.; Maradit Kremers, H.; Mayes, M. D.; Merkel, P. A.; Pillemer, S. R.;
Reveille, J. D.; Stone, J. H. Arthritis Rheum. 2008, 58, 15.
2. Symmons, D. P.; Mathers, C. D.; Pfleger, B. The Global Burden of Osteoarthritis
in the Year 2000, GBD 2000 Working Paper, World Health Organisation,
Geneva, http://www.who.int/healthinfo/statistics/bod_osteoarthritis.pdf.