Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) is an important mechanism of...
1
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoural immune resistance. 1 Many human tumours constitutively express the enzyme. 2 IDO1 inhibition has accordingly been an active area of research in drug development. 3 Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalysing the first step of tryptophan degradation, is as well expressed in many tumours, where it prevents their rejection by means of locally depleting tryptophan. 4 The complementary role of tryptophan catabolites in this process was demonstrated by others. 5 We therefore set out to develop new, improved TDO inhibitors using as the starting point the only, unoptimised series previously known in the literature. 6 NAMEDIC 3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY Eduard Dolušić, a Luc Pilotte, b Laurence Moineaux, a Pierre Larrieu, b Vincent Stroobant, b Didier Colau, b Lionel Pochet, a Etienne De Plaen, b Catherine Uyttenhove, b Benoît Van den Eynde, b Johan Wouters, a Bernard Masereel, a Steve Lanners a and Raphaël Frédérick a 1 ) Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, B-5000 Namur, Belgium 2 ) Ludwig Institute for Cancer Research, Brussels Branch, and de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium [email protected] 1. Introduction 2. Synthesis and SAR 7 me 1. Synthetic schemes for (2-pyridin-3-yl)vinylarenes Table 1. TDO inhibitory potency of analogues 3 - 41. IC 50 values tested in cells transfected with mouse TDO (mTDO) Scheme 2. Synthetic schemes for modifications of the side chain Scheme 3. Synthetic schemes for linker modifications comp . Ar mTDO IC 50 / [mM] comp. R mTDO IC 50 / [mM] comp . R mTDO IC 50 / [mM] comp . R mTDO IC 50 / [mM] 30 6 1 12 1-Me, 6- F >200 22 5-Cl 20 32 6-Br >200 3 1 13 2-Me >200 23 5-Br 40 33 6-Me >200 4 >200 14 2-Ph >200 24 5-Me >200 34 6-OMe >200 5 >200 15 4-F 10 25 5-OMe >200 35 6-OH >200 6 >200 16 4-Cl >40 26 5-CN >200 36 6-CO 2 Me >200 7 18 17 4-Br >200 27 5-NO 2 >200 37 7-F 50 - 100 8 >200 18 4-CN >200 28 5-CO 2 Me >200 38 7-Cl >200 9 >200 19 4-NO 2 >200 29 5-CO 2 H >200 39 7-Br >20 10 >200 20 4-CO 2 Me >200 30 6-F 1 40 7-Me >200 11 >200 21 5-F 5 31 6-Cl 20 41 7-OMe >200 Table 2. TDO inhibitory potency of indole derivatives with different side chains (tested as above) comp . R R' R'' mTDO IC 50 / [mM] comp. R R' R'' mTDO IC 50 / [mM] comp . R R' R'' mTDO IC 50 / [mM] 3 H H 1 49 F 3-F-Ph H 10 58 F H 2 30 F H 1 50 F 3-Cl-Ph H >200 59 F CO 2 Me H 2 42 H H 20 51 F 3-Br-Ph H >200 60 H CO 2 H H 18 43 F H 3 52 F 3-OMe- Ph H 10 61 F CO 2 H H 3 44 H H 20 53 F 3-CN-Ph H 1 62 F CH 2 OH H 80 45 F H 3 54 F 3-NO 2 -Ph H 3 64 F Ph CN >80 46 H Me H >80 55- trans H CN H 13 65 F CO 2 Et CN >80 47 F Ph H 40 56- trans F CN H 3 66 F CO 2 H CN >80 48 F H >200 57 H H 10 67 F CO 2 H CO 2 H >80 Table 3. TDO inhibitory potency of indole derivatives with different linkers (tested as above) comp. X R mTDO IC 50 / [mM] comp . X R mTDO IC 50 / [mM] 3 1 73 CN >80 68 80 74 CN 44 69 6 57 10 55- trans CN 13 75 >80 55-cis CN >80 76 >80 71 CN >80 77 >80 72 CN >80 78 >80 Table 5. Oral bioavailability of 30 and 58 in mice (administr. 160 mg/kg/day) 8 30 58 = LM 10 Figure 1. View of 58 docked inside the TDO binding cleft 7 Table 4. Exp. solubility and stability for 30, 58 and 61 7 Figure 2. Reversal of tumoural immune resistance by systemic inhibition of TDO 8 3. Docking, physicochemistry and in vivo properties 1) Munn, D. H. and Mellor, A. L., J. Clin. Invest. 2007, 117, 1147-1154; Katz, J. B., et al, Immunol. Rev. 2008, 222, 206- 221; Prendergast, G. C., Oncogene 2008, 27, 3889-3900. 2) Uyttenhove, C., et al, Nat. Med. 2003, 9, 1269-1274. 3) Macchiarulo, A., et al, Amino Acids 2009, 37, 219-229; Liu, X., et al, Blood 2010, 115, 3520-3530; Röhrig, U. F., et al, J. Med. Chem. 2010, 53, 1172-1189; Dolušić, E., et al, Bioorg. Med. Chem. 2011, 19, 1550-1561. 4) Van den Eynde, B., et al, WO2010008427, 2010; 5) Opitz, C. A., et al, Nature 2011, 478, 197-203; 6) Madge, D. G., et al, Bioorg. Med. Chem. Lett. 1996, 6, 857-860. 7) Dolušić, E., et al, J. Med. Chem. 2011, 54, 5320-5334; Moineaux, L., et al, Eur. J. Med. Chem. 2012, 54, 95-102; 8) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 – 2502. This work was supported in part by FNRS-Télévie (7.4.543.07). 4. References R' O HO N H 42-45,47-56 R R' CO 2 CH 3 59 N H F CO 2 CH 3 N H F CO 2 H 61 N H 57-58 R NH N N N N H H R R = F orH N H F N B S O O O O N H CH 3 46 N H F 62 OH N H F R' R'' 64-67 O N F N 63 piperidine Et 3 N ,solvent, 25 -94% 1.AlC l 3 /NaN 3 TH F, ,2 h 2. 55-trans or 56-trans ,18 h,26 -64% ; Ph 1. Pd(PPh 3 ) 4, aq N a 2 CO 3 toluene, mW (120°C ),30' Br 2.KO H ,H 2 O /M eOH ,18 h 54% Pd(O A c) 2 C u(O Ac) 2 DM F/DM SO 9/1 70°C ,18 h,79% ; KOH H 2 O/EtOH ,1 h, 82% D IB AL,toluene -78°C ,30',37% 1.P O C l 3 /DM F 2.aq.N aO H 3.pyrrolidine,toluene ,2.5 h,98% RCH 2 R',pyridine, rt,1 -20 h,3 -96% or RCH 2 R ',Et 3 N EtO H ,rt,19 h,81% N H R 3,55- cis ,57 N H R 68,73,77 N Br S O O N Si N H 69 N N N H N 70 N H SCN 74 N H X CN N H X HN N N N 71,X = - 72,X = CH 2 74,X = (CH 2 ) 2 S H 2 (1 atm ) 3% Pd/C EtO H /THF,rt 1 to 3 days 36 -92% Ph 1. P d(O Ac) 2, NaOAc PPh 3, ( n-H ex) 4 NCl D M F, mW 100°C ,15 m in 2.sat.aq N aH CO 3 M eO H ,60°C ,72 h 58% 1.LD A,TH F/hexanes -78 to 0°C ,1 h N H Br TH F/hexanes 0°C to rt,20 h 75% 2. N H N KSCN,( n-Bu) 4 NBr TH F, ,24 h ~quant. 1.AlC l 3 /NaN 3, TH F, ,2 h 2. 71 or 72, ,21 h,66 -67% or 74,N aN 3 /ZnBr 2 i -PrO H/H 2 O ,6 h,70% 75,X = - 76,X = CH 2 78,X = (CH 2 ) 2 S 28 , Ar= N Ar O H O HO . HCl Ar N 3, 5-10, 12-41 N H O O * N H HO O * 29 , Ar= N N H Br N H N 4 N O H O H N H P(Ph) 3 N 11 N H Br Br 4' 11' 2 Br Ar H 1 2 1.P O C l 3 /DM F 2.aq.N aO H piperidine Et 3 N ,solvent, 8 -96% 2M aq N aO H M eO H /THF 60°C ,3 h,65% TMSCHN 2, i -PrO H, Ph 3 P ,60°C ,24 h,30% Cu ++ N N Cl - Cl - P d(O Ac) 2, Ph 3 P ,( i -Pr) 2 NH, NM P,140°C ,18 h,17% ~quant. PPh 3, CH 3 CN ,7 h ~quant. NaH ,TH F,rt,30' 69% of~1:1 trans/cis mix.
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Transcript of Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) is an important mechanism of...
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoural immune resistance.1 Many human tumours constitutively express the enzyme.2 IDO1 inhibition has accordingly been an active area of research in drug development.3
Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalysing the first step of tryptophan degradation, is as well expressed in many tumours, where it prevents their rejection by means of locally depleting tryptophan.4 The complementary role of tryptophan catabolites in this process was demonstrated by others.5
We therefore set out to develop new, improved TDO inhibitors using as the starting point the only, unoptimised series previously known in the literature.6
NAMEDIC
3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORSFOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY
Eduard Dolušić,a Luc Pilotte,b Laurence Moineaux,a Pierre Larrieu,b Vincent Stroobant,b Didier Colau,b Lionel Pochet,a Etienne De Plaen,b Catherine Uyttenhove,b
Benoît Van den Eynde,b Johan Wouters,a Bernard Masereel,a Steve Lannersa and Raphaël Frédéricka
1) Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, B-5000 Namur, Belgium2) Ludwig Institute for Cancer Research, Brussels Branch, and de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium
1. Introduction
2. Synthesis and SAR7
Scheme 1. Synthetic schemes for (2-pyridin-3-yl)vinylarenes
Table 1. TDO inhibitory potency of analogues 3 - 41. IC50 values tested in cells transfected with mouse TDO (mTDO)
R'
O
HONH
42-45, 47-56
R
R'
CO2CH3
59NHF
CO2CH3
NHF
CO2H
61
NH
57-58
RNH
NNN
NH
H
R
R = F or H
NHF
N
B
SOO
OO
NH
CH3
46
NHF
62
OH
NHF
R'
R''
64-67
O
NF
N
63
piperidineEt3N, solvent,
25 - 94%
1. AlCl3/NaN3THF, , 2 h
2. 55-trans or 56-trans, 18 h, 26 - 64%;
Ph
1.
Pd(PPh3)4, aq Na2CO3toluene, W (120°C), 30'
Br
2. KOH, H2O/MeOH, 18 h
54%
Pd(OAc)2Cu(OAc)2
DMF/DMSO 9/170°C, 18 h, 79%;
KOHH2O/EtOH
, 1 h,82%
DIBAL, toluene-78°C, 30', 37%
1. POCl3/DMF2. aq. NaOH3. pyrrolidine, toluene , 2.5 h, 98%
RCH2R', pyridine,rt, 1 - 20 h, 3 - 96%
or RCH2R', Et3NEtOH, rt, 19 h, 81%
Scheme 2. Synthetic schemes for modifications of the side chain
Scheme 3. Synthetic schemes forlinker modifications
NH
R
3, 55-cis, 57
NH
R
68,73, 77
N
Br
S OO
NSi
NH
69
N
N
NH
N
70
NH
SCN
74
NH
X CN
NH
X
HN NN
N
71, X = -72, X = CH274, X = (CH2)2S
H2 (1 atm)3% Pd/C
EtOH/THF, rt1 to 3 days36 - 92%
Ph
1.
Pd(OAc)2, NaOAcPPh3, (n-Hex)4NClDMF, W 100°C, 15 min
2. sat. aq NaHCO3MeOH, 60°C, 72 h
58%
1. LDA, THF/hexanes-78 to 0°C, 1 h
NH
Br
THF/hexanes0°C to rt, 20 h
75%
2.
x
NH
NKSCN, (n-Bu)4NBrTHF, , 24 h
~quant.
1. AlCl3/NaN3, THF, , 2 h2. 71 or 72, , 21 h, 66 - 67%
or 74, NaN3/ZnBr2i-PrOH/H2O, 6 h, 70%
75, X = -76, X = CH278, X = (CH2)2S
comp. Ar mTDO IC50 / [M] comp. R mTDO
IC50 / [M] comp. R mTDO IC50 / [M] comp. R mTDO
IC50 / [M]
306 1 12 1-Me, 6-F >200 22 5-Cl 20 32 6-Br >200
3 1 13 2-Me >200 23 5-Br 40 33 6-Me >200
4 >200 14 2-Ph >200 24 5-Me >200 34 6-OMe >200
5 >200 15 4-F 10 25 5-OMe >200 35 6-OH >200
6 >200 16 4-Cl >40 26 5-CN >200 36 6-CO2Me >200
7 18 17 4-Br >200 27 5-NO2 >200 37 7-F 50 - 100
8 >200 18 4-CN >200 28 5-CO2Me >200 38 7-Cl >200
9 >200 19 4-NO2 >200 29 5-CO2H >200 39 7-Br >20
10 >200 20 4-CO2Me >200 30 6-F 1 40 7-Me >200
11 >200 21 5-F 5 31 6-Cl 20 41 7-OMe >200
Table 2. TDO inhibitory potency of indole derivativeswith different side chains (tested as above)
comp. R R' R'' mTDO IC50 / [M] comp. R R' R'' mTDO
IC50 / [M] comp. R R' R'' mTDO IC50 / [M]
3 H H 1 49 F 3-F-Ph H 10 58 F H 2
30 F H 1 50 F 3-Cl-Ph H >200 59 F CO2Me H 2
42 H H 20 51 F 3-Br-Ph H >200 60 H CO2H H 18
43 F H 3 52 F 3-OMe-Ph H 10 61 F CO2H H 3
44 H H 20 53 F 3-CN-Ph H 1 62 F CH2OH H 80
45 F H 3 54 F 3-NO2-Ph H 3 64 F Ph CN >80
46 H Me H >80 55-trans H CN H 13 65 F CO2Et CN >80
47 F Ph H 40 56-trans F CN H 3 66 F CO2H CN >80
48 F H >200 57 H H 10 67 F CO2H CO2H >80
Table 3. TDO inhibitory potency of indolederivatives with different linkers (tested as above)
comp. X R mTDO IC50 / [M] comp. X R mTDO
IC50 / [M]
3 1 73 CN >80
68 80 74 CN 44
69 6 57 10
55-trans CN 13 75 >80
55-cis CN >80 76 >80
71 CN >80 77 >80
72 CN >80 78 >80
28, Ar =
N
Ar
OH
O
HO.HCl
Ar
N
3,5-10,12-41
NH
O
O *
NH
HO
O *
29, Ar =
N
NH
Br
NH
N
4N
O
H
O
H
NH
P(Ph)3 N
11NH
Br
Br
4'
11'
2 Br
ArH
1 2
1. POCl3/DMF2. aq. NaOH
piperidineEt3N, solvent,
8 - 96%
2M aq NaOHMeOH/THF
60°C, 3 h, 65%
TMSCHN2, i-PrOH,Ph3P, 60°C, 24 h, 30%
Cu++
N N
Cl-Cl-
Pd(OAc)2, Ph3P, (i-Pr)2NH,NMP, 140°C, 18 h, 17%
~quant.
PPh3, CH3CN, 7 h
~quant.NaH, THF, rt, 30'
69% of ~1:1 trans/cis mix.
Table 5. Oral bioavailability of 30 and 58 in mice (administr. 160 mg/kg/day)8
30 58 = LM 10
Figure 1. View of 58 dockedinside the TDO binding cleft7
Table 4. Exp. solubility and stability for 30, 58 and 617
Figure 2. Reversal of tumoural immune resistance by systemic inhibition of TDO8
3. Docking, physicochemistry and in
vivo properties
1) Munn, D. H. and Mellor, A. L., J. Clin. Invest. 2007, 117, 1147-1154; Katz, J. B., et al, Immunol. Rev. 2008, 222, 206-221; Prendergast, G. C., Oncogene 2008, 27, 3889-3900.2) Uyttenhove, C., et al, Nat. Med. 2003, 9, 1269-1274.3) Macchiarulo, A., et al, Amino Acids 2009, 37, 219-229; Liu, X., et al, Blood 2010, 115, 3520-3530; Röhrig, U. F., et al, J. Med. Chem. 2010, 53, 1172-1189; Dolušić, E., et al, Bioorg. Med. Chem. 2011, 19, 1550-1561.4) Van den Eynde, B., et al, WO2010008427, 2010;5) Opitz, C. A., et al, Nature 2011, 478, 197-203;6) Madge, D. G., et al, Bioorg. Med. Chem. Lett. 1996, 6, 857-860.7) Dolušić, E., et al, J. Med. Chem. 2011, 54, 5320-5334; Moineaux, L., et al, Eur. J. Med. Chem. 2012, 54, 95-102;8) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 – 2502.This work was supported in part by FNRS-Télévie (7.4.543.07).
4. References
