1-SAR around small molecules.indd

SAR around small molecules as LFA-1 antagonists
D. Potin a, M. Launay a, E. Nicolai a, M. Mailleta, M. Fabreguettea, A. Fouquet a, P. Malabre a, F. Monatlik a, F. Caussade a, D. Besse a,
S. Skala b, D. K. Stetsko b, D. L. Hollenbaugh, M. Mckinnon b, J. C. Barrish b, E. J. Iwanowicz b, S. J. Suchard b and T.G. M. Dhar b
a
b
Cerep, 19 avenue du Québec, 91951 Courtabœuf cedex - France - tel. +33 (0)1 60 92 60 00 - www.cerep.com
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000 - USA
LFA-1 (Leukocyte Function Associated Antigen-1), is a member of the β2-integrin family
and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells
and antigen-presenting cells.
Evidence from both animal models and clinical trials provides support for LFA-1 as
a target in several different immune or inflammatory diseases 1. Efalizumab (Raptiva®) was approved in 2003 in US for moderate-to-severe psoriasis. Because of the therapeutic potential of the inhibition of LFA-1-mediated immune response, there has been
an intense effort to identify orally available, small molecule inhibitors of this interaction 2 (Fig.1).
Last-Barney et al. 3 have postulated a binding model of BIRT-377 bound to LFA-1 wherein the inhibitor adopts a conformation orienting the 3,5-dichlorophenyl and the p-bromophenyl aromatic rings in a favorable edge-to-face interaction. The two compounds
(I) and (II) 4 are constrained analogues of BIRT-377.
To study the influence of this conformation on the potency of the compounds, other conformationally constrained analogues were
synthesized, employing rigid bicyclic systems (Fig. 2).
Fig-1: Analogs from several recently disclosed, structurally diverse chemical series
Cl
Me
Me
N
Me
O
O
H
Me
S
LFA-703
Me
N
compound A
NCO
R1
A
Y
NH(Boc)2
Ar 1
NaH / DMF
Boc
Ar 1
X
N- Na+
Y
A
A
N
H
DCM
A
DMF
O
R2
HN
HCl
Ar
N- Na+
R1
N
N
Boc
N
reflux
2/ MeONa
MeOH
R2
Scheme B
R1
O R 1 / KOH aq.
N
H
O
Toluene
X
compound B
RCONHNH2
NH
R1
+
2
Ar 1
R1
Cpd.
type
A r1
N
N
A
N
O
R2
O
NCO
R1
1/ DCM
+
1
N
2/ CDI
R2
R2
A r1
N
A
N
O
O
1/ Et2O
O
N
2/ Ac2O/NaOAc
R2
R1
H N
2
S iM e3
ClCH2SiMe3
Ar 1
MeCN/Et3N
N
H
O
H
MeOH
N
DCM
N
A r1
N
R1
R2
M e 3S i
HCHO
A r1
O
TFA
R2
O
H
O
A r1
M eO
Scheme D
O
O
N
compounds C and D
R1
N
R1
CPh3
+
H
N
Toluene
reflux
O
R2
O
O
R2
O
O
R1
N
C Ph3
H+
H
N
H
R2
NH
R1
R3CHO
NaHB(OAc)3
or
R3 X
NaH-DMF
H
O
O
H
N
O
N
Boc
R2
O
R3
N
N
R2
Boc
MeSO3H
N
DCM
N
R1
R1
R2
O
Scheme F
NH
N
R3 X
K2CO3/NaI
MEK
O
N
R1
R2
N
R3
N
OH
Ar-NCO
N
R1
R2
Boc
N
OMs
O
N
1/ B-/THF, R3SH
S R3
HN
2/ H+
M e O 2C
K2CO3/DCM
M eO 2C
M eO 2C
DessMartin
DCM
R1
R2 O
O
HN
MeO2C
O
N
Ar-NCO
DCM/K2CO3
R1
R2
O
O
N
R3R4NH
N
O
S R3
N
Ar-NCO
N R3 R 4
N
AcO3BHNa
R1
R2
O
CONCLUSIONS
■
H1Hela/HSB
A-1
3,5-Cl
O-CH2
4-Br Phenyl
193 nM
A-2
3,5-Cl
O-CO
4-Br Phenyl
798 nM
A-3
3,5-Cl
CH2-CH2
4-Br Phenyl
B-1
3,5-Cl
–
–
B-2
3,5-Cl
–
B-3
3,5-Cl
–
B-4
3,5-Cl
B-5
IC50 or % inhib@1µm
25%
Benzyl
inactive
–
4-Cl Phenetyl
947 nM
–
4-MeO-Benzyl
16%
–
–
4-Br Benzyl
635 nM
3,5-Cl
–
–
B-6
3,5-Cl
–
4-CN Phenyl
C-1
3,5-Cl
–
–
H
12%
C-2
3,5-Cl
–
–
4-Br-Benzyl
5%
C-3
3,5-Cl
–
–
Br
3,5-Cl
–
R1, R2
A
3,5-Cl
O
O
1500 nM
inactive
5%
–
R3
O
4-Br Phenetyl
41%
Stereo
IC50 or % inhib@1µm
7aS,5S
28%
H1Hela/HSB
O
OR 3
N
R3
N
O
MsCl
DCM/TEA
Molecular
modelling was
done to compare
the overlay of
these systems
with BIRT-377
Ac
Ar1
D-1
N
K2CO3/DCM
M e O 2C
2/ H+
Boc
OR3
HN
or DEAD/PPh3 ,
R3OH
C-4 and D-4 over BIRT-377
A
Cpd.
type
O
1/ B-/THF, R3X
compound D
R1, R2
C-4
H
O
O
Ar-NCO
HN
O
Y
Br
N
Scheme E
EtO 2 C
compound C
Z
N
■ In vitro activity of bicyclic compounds
Scheme C
O
N
X
N
O
Z
compound B
A
N
N
A
O
Z
O
A-286982
O
O
H
N
H
N
R1
O
Y
compound A
A
O
X
N
N
X
Me
NH
Cl
O
R2
N
N
■ Various schemes of synthesis of compounds A, B, C and D
Scheme A
O
Y
Y
O
Z
N
N
O
N
N
(I) WO-01300781
A
N
N
NO2
O Me
S
O
Cl
N
O
N
O
Cl
O
HO
O
N
Me
N
O
X
OH
N
(II)
O
Cl
O
N
Cl
Br
Br
BIRT-377
Fig-2
A series of conformationally constrained bicyclic analogs were prepared as
LFA-1 antagonists. Of these, the bicyclic[5.5]hydantoin scaffold that adapts
a "half-open" book conformation led to a series potent LFA-1 antagonists.
Optimization of the length and nature of the linker, stereochemistry at
the 5 and 7a positions of the hydantoin scaffold, led to (D-4) as a potent
inhibitor of the LFA-1/ICAM interaction.
D-2
3,5-Cl
O
4-Br-Phenyl
7aS,5S
480 nM
D-3
3,5-Cl
O
4-Br-Benzyl
7aS,5R
935 nM
D-4
3,5-Cl
O
4-Br-Benzyl
7aS,5S
85 nM
D-5
3,5-Cl
O
4-Br-Benzyl
7aR,5R
275 nM
D-6
3,5-Cl
O
3-Br-Benzyl
7aS,5S
755 nM
D-7
3,5-Cl
O
4-CN-Benzyl
7aS,5S
270 nM
D-8
3,5-Cl
O
4-Cl-Benzyl
7aS,5R
620 nM
D-9
3,5-Cl
O
4-(2-CNPh)-Benzyl
7aS,5S
28%
D-10
3,5-Cl
S
4-Br-Benzyl
7aS,5S
290 nM
D-11
3,5-Cl
NH
4-CN-Benzyl
7aS,5S
175 nM
D-12
3,5-Cl
NH
4-CN-Benzyl
7aS,5R
11%
D-13
3,5-Cl
NH
4-Br Phenetyl
7aS,5S
20%
D-14
3,5-Cl
NH
4-Br Phenetyl
7aS,5R
5%
D-15
3,5-Cl
NMe
4-Br-Benzyl
7aS,5S
175 nM
D-16
3,5-Cl
NEt
4-CN-Benzyl
7aS,5S
730 nM
References
1
2
3
4
Yusuf-Makagiansar H, et al. (2005) Med Res Rev, 22 (2): 146-167
Anderson ME and Siahaan TJ, (2003) Peptides, 24 (3): 487-501
Winquist RJ, et al., (2001) Eur J Pharmacol., 429(1-3): 297-302
Liu, G. (2001), Drugs Future, 26: 767
Last-Barney K., et al. (2001), J. Am. Chem. Soc., 123: 5643-5650
Panzenbeck MJ, et al. (2006), Eur. J. Pharmacol., 534(1-3): 233