Nonpeptide αvβ3 antagonists. Part 9: Improved pharmacokinetic profile through the use of an aliphatic, des-amide backbone

Article abstract of DOI:10.1016/j.bmcl.2004.06.068

A series of α_vβ₃ receptor antagonists lacking the amide bond of previously-reported 'chain-shortened' compounds is described. Replacement of the lone amide bond with two methylene groups in this series yields more lipophilic compound

Full text of DOI:10.1016/j.bmcl.2004.06.068

Bioorganic & MedicinalChemistry Letters 14 (2004) 4411–4415
Nonpeptide avb3 antagonists. Part 9: Improved
pharmacokinetic profile through the use of an aliphatic,
des-amide backbone
a,
David B. Whitman,a, Ben C. Askew, Le T. Duong,b Carmen Fernandez-Metzler,d
*
WasylHaclzenko, George D. Hartman,a John H. Hutchinson,a Chih-Tai Leu,b
Thomayant Prueksaritanont,c Gideon A. Rodan,b Sevgi B. Rodanb and Mark E. Duggana
a
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA
cDepartment of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
dDepartment of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA
Received 23 February 2004; accepted 21 June 2004
Abstract—A series of avb3 receptor antagonists lacking the amide bond of previously-reported Ôchain-shortenedÕ compounds is
described. Replacement of the lone amide bond with two methylene groups in this series yields more lipophilic compounds that have
longer half-lives, lower clearance, and greater oral bioavailability when administered to dogs.
Ó 2004 Elsevier Ltd. All rights reserved.
In the constant process of remodeling bone, cells called
osteoclasts are responsible for bone resorption. Osteo-
blasts balance this process by forming new bone. The
skeletal disease known as osteoporosis occurs when
the activity of osteoclasts increases relative to the activ-
ity of osteoblasts. This leads to a net decrease in bone
density, which makes affected individuals more suscepti-
ble to fractures. Osteoporosis affects primarily post-
menopausalwomen, because increased bone resorption
is associated with a decrease in estrogen levels.1 The in-
tegrin avb3 receptor, which is highly expressed on osteo-
clasts, plays an essential role in the attachment and
migration of these cells during bone resorption. Com-
pounds that bind to the avb3 receptor have been shown
to inhibit bone resorption in vivo.2
to Ôchain-shortenedÕ molecules with a single amide
bond.3–6 These studies showed that the optimaldistance
between the N-terminaltetrahydronaphthyridine nitro-
6
gen and the C-terminalcarboxyilc acid is eight atoms.
Certain arylsubstituents on the carbon atoms aplha
and beta to the carboxylic acid, as well as sulfonamides
at the alpha position, have been shown to significantly
increase affinity for the avb3 receptor in other series.3,7
In this paper we describe the identification of a new class
of chain-shortened compounds that combine some of
these potency-enhancing, alpha-amino substitutions
with replacement of the single remaining amide bond
to further improve the pharmacokinetic characteristics
of the series.
The pathway used to prepare the compounds discussed
here is shown in Scheme 1. Commercially available
methylsebacoylcholride was treated with CuCN and
MeMgBr to form the methylketone, which was then
subjected to a Friedlander condensation with 2-amino-
3-formylpyridine.8 The resulting 1,8-naphthyridine 2
was then hydrogenated and the ester hydrolyzed, yield-
ing the 5,6,7,8-tetrahydro-1,8-naphthyridine 3. Forma-
tion of the mixed anhydride of this carboxylic acid
followed by treatment with the lithium anion of (S)-4-
benzyl-2-oxazolidinone gave the chiral intermediate 4.9
Previous reports from this laboratory have detailed the
progression of avb3 antagonists from proteins contain-
ing an arginine-glycine-aspartic acid (RGD) sequence,
to Ôfull-lengthÕ analogs containing two amide linkages,
*
Corresponding author. Tel.: +1-215-652-4533; fax: +1-215-652-
7310; e-mail: david_whitman@merck.com
Present address: Amgen, Inc., One Amgen Center Drive, Thousand
Oaks, CA 91320-1799, USA.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.068

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D. B. Whitman et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4411–4415
O
Cl
OCH3
O
1
i, ii
O
N
N
OCH3
2
iii, iv
O
H
N
N
OH
3
v
O
H
N
N
N
O
O
4
vi
O
O
H
H
N
N
N
N
N
NH2
N3
N3
O
O
O
7
5
vii, viii
x
O
O
H
N
H
N
N
N
OH
NH2
N3
6
8
xi, xii, xiii
ix
O
H
N
N
OH
HN
R
9 a-j
Scheme 1. Reagents and conditions: (i) CuCN, MeMgBr, THF; (ii) 2-amino-3-formylpyridine, L-(À)-proline, EtOH, (66% yield over two steps); (iii)
10% Pd/C, H2 (1atm), EtOH, (97%); (iv) NaOH, MeOH, (88%); (v) NEt3, trimethylacetylchol ride, then n-BuLi+(S)-4-benzyloxazolidinone, THF;
(vi) KHMDS, 2,4,6-triisopropylbenzenesulfonyl azide; (vii) 10% Pd/C, H2 (1atm), EtOH, (84%); (viii) 6N HCl, (90%); (ix) NaOH, R–Cl or R–NCO,
2:1 H2O–dioxane, (17–57%); (x) Ti(Oi-Pr)4, i-PrOH, (14%); (xi) Ph3P, 3:1 THF–H2O, (62%); (xii) NMM, R–Cl, DCM, (28–98%); (xiii) 6N HCl,
dioxane, (51–99%).
Treatment of
4
with KHMDS and 2,4,6-tri-
Alternately, the 2-azido-1-benzyloxazolidinone 7 was
treated with titanium isopropoxide in isopropanolto
form the isopropylester 8. After Staudinger reduction
of the azide, the resulting amine was treated with the
appropriate alkylating agent and N-methylmorpholine
in dichloromethane. Hydrolysis of the ester was then
accomplished by heating with 6N HCl to generate the
compounds obtained through this variation of the syn-
thetic scheme.
isopropylbenzenesulfonyl azide gave the desired 2(S)-
azido-4(S)-benzyloxazolidinone 7 with high diastereo-
selectivity. Unexpectedly, the reaction also yielded the
primary amide 5 in a ratio of approximately 1:1 with
compound 7. The azide 5 was reduced with palladium
on carbon and the primary amide hydrolyzed to the car-
boxylic acid 6 by mild heating in 6N HCl. Alkylations
of 6 were performed under typicalSchotten–Baumann
conditions using the appropriate sulfonyl chloride, acid
chloride, chloroformate, or isocyanate to yield the target
compounds.
Table 1 shows the key data for severalaplha-amino
substitutions in the chain-shortened series of com-

D. B. Whitman et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4411–4415
4413
pounds.10–12 Although some of these compounds
achieved the desired sub-nanomolar potency in the
SPAV3 assay, their pharmacokinetic profiles were less
than optimal. When dosed to dogs, half-lives of the
compounds were generally short, and oral bioavailability
was very low.
Acylation of the amine to generate the phenylacetyl-
amino (9i) and benzoylamino (9j) compounds produced
analogs with extremely long half-lives of 19.2 and 17.9h,
respectively. However, these compounds had reduced
affinity for the avb3 receptor compared to the sulfona-
mides. A similar effect was seen in the series of
compounds with the amide-containing backbone.
It was hypothesized that deletion of the lone amide
bond, while maintaining the overall length of the mole-
cule, might improve the pharmacokinetic profile of the
chain-shortened compounds. A comparison of the Log
P values of the compounds in Tables 1 and 2 shows that
this modification causes a significant increase in lipophi-
licity, but in both series, all of the compounds tested had
human protein binding values >97%. The des-amide
analogs shown in Table 2 were less potent in the
SPAV3 assay than their amide counterparts; however,
the pharmacokinetic profiles in dogs were signifi-
cantly improved. The phenylsulfonamide compound 9d
exhibited a plasma half-life of 9.3h, with low clearance
(7mL/min/kg). When dosed orally, the bioavailability
(F) was 55%, approximately an eightfold improvement
over the analogous amide 10c. The CBZ-amine 9c
showed a similar increase in oral bioavailability, but
its half-life was only slightly better than the comparable
The use of a camphorsulfonyl group in avb3 antagonists
has been reported previously.1 In both the amide and
the des-amide series shown here, the camphorsulfon-
amide compounds (9a and 10a) were the most potent
in the SPAV3 assay. Unfortunately, this functionality
also caused a reduction in both half-life and bioavail-
ability in this series.
The prepared compounds were also tested in a platelet
aggregation assay and found to be selective against the
fibrinogen receptor, aIIBb3, which is a related integrin
that shares the same b subunit as avb3.
In conclusion, we have identified a new class of potent
avb3 receptor antagonists that possesses an improved
pharmacokinetic profile over an earlier series of chain-
shortened compounds. By replacing the amide bond
with two methylene groups, the overall length is main-
tained, permitting favorable binding interactions with
the receptor. This substitution makes the resulting des-
amide compounds more lipophilic and leads to longer
amide 10b. The aliphatic n-butylsufolnamide
9f,
although not quite as potent, had an excellent half-life
of 8.1h and the highest oralbioavaial biilty of the series
(91%).
Table 1. Chain-shortened avb3 receptor antagonists: potency, Log P, and pharmacokinetic parameters in dogs10–12
O
O
H
N
N
N
OH
H
HN
R
R
Compound
SPAV3 (IC50, nM)
Log P
T1/2 (h)
Cl(mL/min/kg)
22
F (%)
O
S
10a
0.1
––
0.4
1
O
H
O
O
10b
1.8
0.32
1.2
10
5
O
O
S
10c
10d
0.3
2.3
À0.38
À0.44
0.7
––
29
––
7
O
O
S
––
O
10e
10f
73.8
0.4
À0.23
––
––
13
––
O
O
S
0.08
1.2
<1
O

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D. B. Whitman et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4411–4415
Table 2. Chain-shortened, des-amide avb3 receptor antagonists: potency, Log P, and pharmacokinetic parameters in dogs10,11
R
Compound
SPAV3 (IC50, nM)
Log P
T1/2 (h)
Cl(mL/min/kg)
12
F (%)
O
S
9a
0.8
1.18
0.4
2
O
H
O
H
N
9b
9c
4.7
6.1
1.44
1.89
1.8
1.8
10
5
31
61
O
O
O
O
S
9d
11.2
1.05
9.3
7
55
O
O
S
9e
9f
18.1
21.3
1.69
0.95
1.9
8.1
7
4
77
91
O
O
S
O
O
S
9g
34.5
1.16
3.2
11
33
O
O
S
9h
9i
49.8
51.6
––
––
––
13
––
17
O
1.13
19.2
O
O
9j
71.7
1.29
17.9
1
36
R. M.; Perkins, J. J.; Rodan, S. B.; Wesolowski, G.;
Whitman, D. B.; Zartman, A. E.; Rodan, G. A.; Hartman,
G. D. J. Med. Chem. 2000, 43, 3736–3745.
half-lives, lower clearance, and increased oral bioavail-
ability when administered to dogs.
4. Meissner, R. S.; Perkins, J. J.; Duong, L. T.; Hartman,
G. D.; Hoffman, W. F.; Huff, J. R.; Ihle, N. C.; Leu, C.;
Nagy, R. M.; Naylor-Olsen, A.; Rodan, G. A.; Rodan, S.
G.; Whitman, D. B.; Wesolowski, G. A.; Duggan, M. E.
Bioorg. Med. Chem. Lett. 2002, 12, 25–29.
5. Coleman, P. J.; Brashear, K. M.; Hunt, C. A.; Hoffman,
W. F.; Hutchinson, J. H.; Breslin, M. J.; McVean, C. A.;
Askew, B. C.; Hartman, G. D.; Rodan, S. G.; Rodan, G.
A.; Leu, C.; Prueksaritanont, T.; Fernandez-Metzler, C.;
Ma, B.; Libby, L. A.; Merkle, K. M.; Stump, G. L.;
Wallace, A. A.; Lynch, J. J.; Lynch, R.; Duggan, M. E.
Bioorg. Med. Chem. Lett. 2002, 12, 31–34.
Acknowledgements
The authors would like to thank the mass spectrometry
and analytical groups for their assistance and also the
Pharmacology Department staff of Dr. Joseph J. Lynch
for administering the compounds to dogs.
References and notes
1. Duggan, M. E.; Hutchinson, J. H. Exp. Opin. Ther.
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Whitman, D. B.; Perkins, J. J.; Hartman, G. D.; Rodan,
G. A.; Leu, C.; Prueksaritanont, T.; Fernandez-Metzler,
C.; Merkle, K. M.; Lynch, R.; Lynch, J. J.; Rodan, S. B.;
Duggan, M. E. Bioorg. Med. Chem. Lett. 2002, 12,
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D. B. Whitman et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4411–4415
4415
7. Brashear, K. M.; Hunt, C. A.; Kucer, B. T.; Duggan,
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8. The 2-methyl-1,8-naphthyridine regioisomer (methyl 8-(2-
methyl-1,8-naphthyridin-3-yl)octanoate, in this case) typ-
ically generated in these Friedlander condensations was
formed in a ratio of approximately 1:3 to desired product.
It was easily separable by flash chromatography on silica
gel.
10. Dogs were dosed at 1mpk po and 0.2mpk iv. All animal
studies described in this report were approved by the
Merck Research Laboratories InstitutionalAnimalCare
and Use Committee.
11. SPAV3 is a scintillation-proximity assay, which measures
the ability of a compound to bind to the avb3 receptor
by displacing 3-{4-[2-(6-aminopyridin-6-yl)ethyl]benzoyl-
amino}-2(S)-4-125iodobenzenesulfonylaminopropionic acid
from purified recombinant human avb3. The procedure is
described in Refs. 3,12.
12. A representative synthesis of the chain-shortened com-
pounds listed in Table 1 is described in Merck and Co.,
Inc. U.S. Patent 6,048,861; 2000.
9. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L.
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