Cyclic peptides targeting alpha-4-beta-7 integrin
There is described herein antagonists of α4β7 integrin, and more particularly to cyclic peptide antagonists. Accordingly, there is described herein a compound of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are various substituents; stereocentres 1*, 2* and 3* are each independently selected from R and S; n is 1, 2, 3, or 4 and where n is 2-4, Z is an amino terminus of an amino acid; —C═O— adjacent L is the carboxy terminus of an amino acid; and L along with Z and —C═O— is a peptide.
1. A compound of formula (I):
wherein
R 1 is H; C 1 -C 6 alkyl; aryl; heteroaryl; alkenyl; or heterocycle; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl;
and where the one or more substituents is not alkyl when R 1 is C 1 -C 6 alkyl;
R 2 and R 3 are each independently an amino acid side chain of a proteinogenic or a non-proteinogenic alpha-amino acid, or
R 2 and R 3 are covalently linked to each other to form a ring;
R 4 and R 5 are each independently H; C 1 -C 6 alkyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula —C(O)OH; esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl; amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; —CH 2 C(O)R, wherein R is selected from —OH, C 1 -C 6 alkyl, aryl, —C 1 -C 6 alkyl-aryl, or NR a R b , where R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl; or —C(O)R c , wherein R c is selected from C 1 -C 6 alkyl, aryl or —C 1 -C 6 alkyl-aryl; or —C 1 -C 6 alkyl-OR d , wherein R d is an OH group or a protecting group selected from the group consisting of formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, benzenesulfonyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, alpha.-,alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, benzyl, triphenylmethyl, benzyloxymethyl, and trimethylsilyl; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl; and where, when R 4 , R 5 , R, R a , R b or R c is C 1 -C 6 alkyl, the one or more substituents is not alkyl at that position; and wherein the one or more substituents is not —NR a R b when R is —NR a R b ;
or R 2 or R 3 are covalently linked to R 1 to form a cyclic secondary amine, and/or to R 4 or R 5 to form a ring, or R 4 and R 5 are covalently linked to each other to form a ring;
R 6 is H, C 1 -C 6 alkyl, benzyl, alkenyl, C 1 -C 6 alkyloxy; aryl; heteroaryl; heterocycle; —C(O)R****, wherein R**** is independently selected from alkyl, aryl, heteroaryl, amino, aminoalkyl, aminoaryl, aminoheteroaryl, alkoxy, aryloxy, heteroaryloxy; —CH 2 C(O)R; or —C(O)R c ; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl, and where the one or more substituents is not alkyl when R 6 is C 1 -C 6 alkyl,
or R 6 forms, along with R 7 or R 8 , a cyclic side chain of a proteinogenic or a non-proteinogenic amino acid having, the N-terminus thereof being the N—R 6 , wherein the proteinogenic or a non-proteinogenic amino acid is optionally substituted with a substituent selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl;
R 7 and R 8 are independently selected from the amino acid side chains of a proteinogenic or a non-proteinogenic alpha-amino acid having the N-terminus thereof being the N—R 6 , or R 7 or R 8 forms a cyclic side chain with R 6 ;
stereocenters 1*, 2* and 3*, where present, are each independently selected from R and S;
n is 1, 2, 3, or 4 and where n is 2-4, each R 7 and each R 8 are independent of each other;
and
wherein Z is an amino terminus of an amino acid; —C═O— adjacent L is the carboxy terminus of an amino acid; and L along with Z and —C═O— is a peptide having the following formula:
X y —X z —X 1 —X 2 —X 3
wherein X y and X z are each independently a proteinogenic or non-proteinogenic amino acid, or X z is absent;
X 1 is Leucine or tert-butyl-Ala;
X 2 is Asp; and
X 3 is an amino acid selected from the group consisting of Thr, Thr(OBn), Thr(OEt), Pen, MeThr, alloThr, Abu, Val, Ile and Allolle,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 or R 3 is covalently linked to R 1 to form proline having NR 1 as the N-terminus.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are not both H.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from the group consisting of amino acid side chains of a proteinogenic or a non-proteinogenic alpha-amino acids.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are H and CH 3 respectively or vice versa.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 or R 3 is —CH 2 —S—R 5 , wherein R 5 is selected from C 1 -C 6 alkyl; C 1 -C 6 amino alkyl; aryl; heteroaryl; alkenyl; or heterocycle; all of which are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ester, ether, thioether, thioalkoxy, phosphino, and —NR a R b ,
wherein R a and R b are independently selected from C 1 -C 6 alkyl, aryl or benzyl; wherein the one or more substituents is not alkyl when R 5 is C 1 -C 6 alkyl; preferably R 5 is phenyl or phenyl substituted with C 1 -C 6 alkyl, halogen; or C 1 -C 6 amino alkyl.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are not both H.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R** and R*** are not both H.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently H, or C(O)—NHR 1 , wherein R 1 is H or a C 1 -C 6 alkyl.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is tert-butyl.
12. The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein R 1 is H.
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 and either R 7 or R 8 form a ring resulting in a proline residue having N—R 6 as its N-terminus.
15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.
16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z along with L and —C═O is any one of SEQ ID NOs. 1-380.
17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 is Leu.
18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 2 is Asp.
19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 is Thr.
20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 is Val.
21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 is Ile.
22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X y and X z are each independently a proteinogenic or non-proteinogenic alpha-amino acid.
23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X z is a proteinogenic or non-proteinogenic beta-amino acid.
24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X z is betaHomoLys or MethylbetaHomoLys.
25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X y and X z are each a primary amino acid.
26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X y and X z are selected from the group consisting of:
X y
X z
Y
absent
H
absent
Y
absent
Y
absent
F
absent
HomoPhe
absent
Cha
absent
W
absent
1Nal
absent
2Nal
absent
W
absent
Bip
absent
Tyr(OPh)
absent
1Nal
absent
2Nal
absent
2Nal
absent
W
absent
Bip
absent
Tyr(2-tolyl diaryl ether)
absent
Tyr(4-CF3 diaryl ether)
absent
Tyr(4-methoxy diaryl ether)
absent
Tyr(4-fluoro diaryl ether)
absent
Tyr(2-methoxy diaryl ether)
absent
Tyr(3-methoxy diaryl ether)
absent
Tyr(3-fluoro diaryl ether)
absent
Tyr(3,4-difluoro diaryl ether)
absent
Tyr(3-methyl diaryl ether)
absent
Tyr(3,4-dimethyl diaryl ether)
absent
Tyr(4-CO2Me diaryl ether)
absent
Tyr(3-CO2Me diaryl ether)
absent
Tyr(4-CO2H diaryl ether)
absent
F
absent
metaY(Opr)
absent
Orn(benzamide)
absent
Orn(acetamide)
absent
Orn(methanesulfonamide)
absent
Orn(ethylcarbamate)
absent
Orn(pentyl amide)
absent
R
absent
F
absent
F
absent
dTyr
absent
dTic
absent
[3-(3′-pyridyl)-Ala]
absent
F
absent
Bip
absent
[3-(3′-pyridyl)-Ala]
absent
Y
absent
Y
absent
dArg
absent
dPip
absent
[3-(4-thiazolyl)-Ala]
absent
Y
absent
(4-aza-Phe)
absent
Y
absent
(vinyl-Br-Leu)
absent
Hyp(OBn)
absent
Hyp(OBn)
absent
Dap(Cbz)
absent
His(Bn)
absent
(4-amino-Phe)
absent
(4-aza-dPhe)
absent
Hyp
absent
dTrp
absent
M
absent
dMet
absent
(4-guanidino-Phe)
absent
(3-aza-Phe)
absent
dTic
absent
(3-aza-dPhe)
absent
Nva
absent
dNle
absent
dLys
absent
dPro
absent
dOrn
absent
(3-benzothienyl-Ala)
absent
dTyr(OAllyl)
absent
dSer(OBn)
absent
[3-(4-thiazolyl)-dAla]
absent
(3-benzothienyl-dAla)
absent
[3-(2-thienyl)-dAla
absent
(4-aminomethyl-Phe)
absent
dOrn(dimethyl)
absent
(4-amino-dPhe)
absent
(4-aminomethyl-dPhe)
absent
dTyr(OBn)
absent
P
absent
cycloLeu
absent
Aic
absent
Tyr(OAllyl)
absent
Chg
absent
K
absent
(2-aza-dPhe)
absent
(2-aza-Phe)
absent
[2-(2-pyridyl)-4-thiazolyl-Ala]
absent
[2-(3-pyridyl)-4-thiazolyl-Ala]
absent
[2-(4-pyridyl)-4-thiazolyl-Ala]
absent
dTiq
absent
[1-(S)-isoindoline-carboxylic acid]
absent
Y
dThr
Y
P
Y
dPro
Y
Sar
Y
cycloLeu
Y
Sar
(3-iodo-Phe)
Sar
(4-iodo-Phe)
Sar
(3,3-diphenyl-Ala)
Sar
F
dLys
Bip
dLys
[3-(4-thiazolyl)-Ala]
dLys
(3,3-diphenyl-Ala)
dLys
Y
dLys
Y
dArg
Y
dSer
Bip
Sar
1Nal
Sar
Y
Pip
(2-iodo-Phe)
Sar
1Nal
dLys
Y
dLys
F
Sar
Y
dTic
Y
dPro
Y
dPip
F
dPro
(3,4-dimethoxy-Phe)
dPro
(3,4,5-trifluoro-Phe)
dPro
(3,5-dibromo-Tyr)
dPro
F
dPip
[3-(4-thiazolyl)-Ala]
dPip
(4-aminomethyl-Phe)
dPip
[2-iodo-Phe]
dPip
(2-phenyl-Phe)
dPip
[2-(2-methoxy-phenyl)-Phe]
dPip
[2-(3-methoxy-phenyl)-Phe]
dPip
[2-(4-methoxy-phenyl)-Phe]
dPip
Bip
dPip
Y
Hyp
Y
dHyp
Y
(cis-dHyp)
dTyr
dPip
1Nal
dPip
2Nal
dPip
(4-aminomethyl-Phe)
dTic
(3-aminomethyl-Phe)
dTic
(3-aminomethyl-dPhe)
dTic
MeTyr
dPip
Y
dPip
Y
dPip
[3-(4-thiazolyl)-Ala]
dHyp
(4-aminomethyl-Phe)
dHyp
Y
dPip
Y
dMeLys
Y
dNle
F
dHyp
Y
dMeArg
Y
G
Y
A
Y
dAla
M
G
Tyr(OAllyl)
Sar
Tyr(OAllyl)
G
[3-(4-thiazolyl)-Ala]
Sar
(4-aminomethyl-Phe)
G
Tyr(OAllyl)
dVal
Tyr(OAllyl)
dSer
Tyr(OAllyl)
dAla
Tyr(OAllyl)
P
Tyr(OAllyl)
dPro
[3-(4-thiazolyl)-Ala]
dVal
[3-(4-thiazolyl)-Ala]
dSer
[3-(4-thiazolyl)-Ala]
dAla
[3-(4-thiazolyl)-Ala]
P
[3-(4-thiazolyl)-Ala]
dPro
(4-aminomethyl-Phe)
P
(4-aminomethyl-Phe)
dPro
cycloLeu
P
[2-(2-pyridyl)-4-thiazolyl-Ala]
Sar
[2-(2-pyridyl)-4-thiazolyl-Ala]
dPro
[2-(3-pyridyl)-4-thiazolyl-Ala]
Sar
[2-(3-pyridyl)-4-thiazolyl-Ala]
dPro
[2-(4-pyridyl)-4-thiazolyl-Ala]
dPro
[3-(2-aminobenzyl-4-thiazolyl)-Ala]
Sar
[2-(amino-benzyl)-4-thiazolyl-Ala]
dPro
dTyr
dPip
(2-aminomethyl-Phe)
Aze
Y
dPip
(3-aminomethyl-Phe)
dTic
(2,4-dichloro-Phe)
dPip
(3-phenyl-dPhe)
dPip
[3-(5-quinolinyl)-dPhe]
dPip
Y
betaHomoLys
Y
betaHomoPro
Y
betaHomoLys
Y
2Abz
F
betaHomoLys
[3-(4-thiazolyl)-Ala]
betaHomoLys
(4-aminomethyl-Phe)
betaHomoLys
Y
betaHomoLys
MeTyr
dbetaHomoLys
1Nal
betaHomoLys
2Nal
betaHomoLys
Bip
betaHomoLys
(2-iodo-Phe)
betaHomoLys
[2-(2,5-dimethyl-isoxazole)-Phe]
betaHomoLys
(2-phenyl-Phe)
betaHomoLys
(2-phenyl-Phe)
betaHomoLys
[(2-piperazinyl-2-Phenyl)-Phe]
betaHomoLys
Cha
betaHomoLys
W
betaHomoLys
dTrp
betaHomoLys
(3-aminomethyl-Phe)
betaHomoLys
(4-aminomethyl-dPhe)
betaHomoLys
(4-aminomethyl-Phe)
betaHomoLys
Y
dbetaHomoLys
dArg
betaHomoLys
(4-aminomethyl-Phe)-reduced
betaHomoLys
[3-(4-thiazolyl)-Ala]
dbetaHomoLys
F
dbetaHomoLys
[3-(4-thiazolyl)-Ala]
MebetaHomoLys
(4-aminomethyl-Phe)
MebetaHomoLys
[3-(4-thiazolyl)-Ala]
betaHomoLys
Tic
betaHomoLys
dTic
betaHomoLys
dTic
dbetaHomoLys
Y
betaHomoIle
(4-aminomethyl-Phe)
betaHomoPro
Y
dbetaHomoPro
(4-aminomethyl-Phe)
dbetaHomoPro
R
betaHomoLys
F
MebetaHomoLys
Phe-reduced
betaHomoLys
(3-aminomethyl-dPhe)
betaHomoLys
[2-[3-(1-piperazinyl)phenyl]-Phe]-
betaHomoLys
betaHomoLys
[3-(4-thiazolyl)-dAla]
betaHomoLys
(2-bromo-Phe)
betaHomoLys
(2-chloro-Phe)
betaHomoLys
(2-fluoro-Phe)
betaHomoLys
(2-CF3-Phe)
betaHomoLys
(2,4-dichloro-Phe)
betaHomoLys
(2-aminomethyl-Phe)
betaHomoLys
[2-(4-quinolinyl)-Phe]
betaHomoLys
[2-(5-quinolinyl)-Phe]
betaHomoLys
[2-(3-quinolinyl)-Phe]
betaHomoLys
dhomoPhe
betaHomoLys
(2-iodo-dPhe)
betaHomoLys
(2-phenyl-dPhe)
betaHomoLys
[(2-piperazinyl-2-Phenyl)-dPhe]
betaHomoLys
Y
betaHomoLys
Y
betaHomoLys
dTyr
betaHomoLys
(4-aminomethyl-dPhe)
betaHomoLys
(4-aminomethyl-Phe)
betaHomoLys
(3-iodo-Phe)
betaHomoLys
(3-phenyl-Phe)
betaHomoLys
[3-(2-methoxy-phenyl)-Phe]
betaHomoLys
[3-(2,6-dimethoxy-phenyl)-Phe]
betaHomoLys
[3-(2-trifluoromethoxy-phenyl)-Phe]
betaHomoLys
(4-iodo-Phe)
betaHomoLys
[4-(2-methoxy-phenyl)-Phe]
betaHomoLys
[4-(2-trifluoromethoxy-phenyl)-Phe]
betaHomoLys
alphaMePhe
betaHomoLys
MePhe
betaHomoLys
[3-(2,6-dimethyl-phenyl)-Phe]
betaHomoLys
[3-(quinolin-4-yl)-Phe]
betaHomoLys
[3-(3,4-difluoro-phenyl)-Phe]
betaHomoLys
[4-(2,6-dimethyl-phenyl)-Phe]
betaHomoLys
[4-(2-chloro-6-methoxy-phenyl)-Phe]
betaHomoLys
[3-(4-thiazolyl)-Ala]-reduced
betaHomoLys
[2-[4-(1-piperazinyl)phenyl]-Phe]
betaHomoLys
[2-(2,6-dimethylphenyl)-Phe]
betaHomoLys
[2-(benzothiazol-5-yl)-Phe]
betaHomoLys
HomoPhe
betaHomoLys
(piperidine-4-amino-4-carboxylic acid)
betaHomoLys
[2-(2,5-dimethyl-isoxazole)-dPhe]
betaHomoLys
dTyr
betaHomoLys
(4-aminomethyl-dPhe)
betaHomoLys
[2-(2-chloro-6-methoxyphenyl)-Phe]
betaHomoLys
2Igl
betaHomoLys
d2Igl
betaHomoLys
Atc
betaHomoLys
Y
betaHomoLys
dTyr
betaHomoLys
(4-aminomethyl-Phe)
betaHomoLys
[2-[2,5-Bis(trifluoromethyl)phenyl]-Phe]
betaHomoLys
[2-[2,5-Bis(trifluoromethyl)phenyl]-Phe]
betaHomoLys
Aic
betaHomoLys
P
betaHomoLys
dPro
betaHomoLys
Pip
betaHomoLys
[2-(3-Pyridyl)-Phe]
betaHomoLys
[2-(4-Pyridyl)-Phe]
betaHomoLys
[2-(3-bromo-2-Pyridyl)-Phe]
betaHomoLys
Y
dbetaHomoLys
(N-benzyl-Gly)
betaHomoLys
[2-(2-bromo-3-Pyridyl)-Phe]
betaHomoLys
[3-(2-chloro-6-methoxy-phenyl)-Phe]
betaHomoLys
[3-(benzothiazol-5-yl)-Phe]
betaHomoLys
(2-aminomethyl-Phe)
MebetaHomoLys
(2-aminomethyl-dPhe)
MebetaHomoLys
[3-(4-thiazolyl)-dAla]
MebetaHomoLys
[2-(2-trifluoromethoxy-phenyl)-dPhe]
MebetaHomoLys
Tic
MebetaHomoLys
dTic
MebetaHomoLys
[2-(5-quinolinyl)-dPhe]
betaHomoLys
Y
betaHomoLys
Y
MebetaHomoLys
MeTyr
MebetaHomoLys
MeTyr
MebetaHomoLys
MePhe
MebetaHomoLys
(2-fluoro-Phe)
MebetaHomoLys
(2-fluoro-MePhe)
MebetaHomoLys
(2,4-dichloro-Phe)
MebetaHomoLys
(2,4-dichloro-MePhe)
MebetaHomoLys
(2-aminomethyl-MePhe)
MebetaHomoLys
[3-(2,6-dimethoxy-phenyl)-dPhe]
betaHomoLys
[3-(4-Quinolinyl)-dPhe]
betaHomoLys
betaHomoLys
Aze
(3-phenyl-dPhe)
betaHomoLys
[3-(2-trifluoromethoxy-phenyl)-dPhe]
betaHomoLys
[3-(2-methoxy-phenyl)-dPhe]
betaHomoLys
[2-(5-quinolinyl)-MePhe]
MebetaHomoLys
F
betaHomoNle
F
MebetaHomoLys(Me)2
MePhe
MebetaHomoLys(Me)2
M
MebetaHomoLys
Igl
MebetaHomoLys
HomoPhe
MebetaHomoLys
Hyp(OBn)
MebetaHomoLys
(1,2-cis-ACHC)
MebetaHomoLys
MeMet
MebetaHomoLys
betaHomoLys
betaHomoLys
BetaHomoPhe
MebetaHomoLys
betahomoMet
MebetaHomoLys
Y
(3-aminomethyl-4-
bromo-benzoic acid)
Y
[3-aminomethyl-4-(4-
aza-phenyl)-benzoic
acid]
Y
[3-aminomethyl-4-
(2,5-dimethyl-
isoxazole)-benzoic
acid]
Y
[3-aminomethyl-4-(3-
aminomethyl-phenyl)-
benzoic acid]
[3-aminomethyl-4-[4-(1-piperazinyl)-phenyl]-
absent
benzoic acid]
[3-aminomethyl-4-(4-quinolinyl)-benzoic acid]
absent
(3-aminomethyl-4-bromo-benzoic acid)
absent
[3-aminomethyl-4-(2,5-dimethyl-isoxazole)-
absent
benzoic acid]
[3-aminomethyl-4-(4-pyridyl)-benzoic acid]
absent
[3-aminomethyl-(4-methylpyrazole-3-yl)-
absent
benzoic acid]
[3-aminomethyl-4-(3-quinolinyl)-benzoic acid]
absent
[3-aminomethyl-4-(5-quinolinyl)-benzoic acid]
absent
[3-aminomethyl-4-[2-(1-piperazinyl)phenyl]-
absent
benzoic acid]
[3-aminomethyl-4-[3-(1-piperazinyl)phenyl]-
absent
benzoic acid]
[3-aminomethyl-4-[2-(3-(piperidin-4-
absent
ylmethoxy)phenyl]-benzoic acid]
[3-aminomethyl-4-(4-pyridyl)-benzoic acid]
absent
[3-aminomethyl-4-(4-pyridyl)-benzoic acid]
absent
[3-aminomethyl-4-(4-quinolinyl)-benzoic acid]
absent
[3-aminomethyl-4-[4-(1-piperazinyl)phenyl]-
absent
benzoic acid]
[3-aminomethyl-4-(4-quinolinyl)]-benzoic acid
absent
[3-aminomethyl-4-[4-(1-piperazinyl-4-
absent
FITC)phenyl]-benzoic acid]
(N-benzyl-3-aminomethyl-benzoic acid)
absent
(3-aminomethyl-benzoic acid)
absent
(3-aminomethyl-5-bromo-benzoic acid)
absent
(3-aminomethyl-6-bromo-benzoic acid)
absent
(3-aminomethyl-4-bromo-benzoic acid)
absent
[3-aminomethyl-5-(4-aza-phenyl)-benzoic
absent
acid]
[3-aminomethyl-4-(3-thiophenyl)-benzoic acid]
absent
[3-aminomethyl-4-(4-N,N-dimethyl-
absent
carboxamide-phenyl)-benzoic acid]
[3-aminomethyl-4-(4-aza-phenyl)-benzoic
absent
acid]
[3-aminomethyl-4-(3-aza-phenyl)-benzoic
absent
acid]
[3-aminomethyl-4-(4-hydroxy-phenyl)-benzoic
absent
acid]
[3-aminomethyl-4-[5-(2,4-dimethyl)thiazole]-
absent
benzoic acid]
[3-aminomethyl-4-(3-N,N-dimethylaniline)-
absent
benzoic acid]
[3-aminomethyl-4-(2-fluoro-pyridyl)-benzoic
absent
acid]
[3-aminomethyl-4-(5-pyrimidinyl)-benzoic acid]
absent
[3-aminomethyl-4-(3-N,N-dimethyl-diaryl
absent
ether)-benzoic acid]
[3-aminomethyl-4-(3-CF3-phenyl)-benzoic
absent
acid]
[3-aminomethyl-4-(2,5-dimethoxy-phenyl)-
absent
benzoic acid]
[3-aminomethyl-4-[(2,3,4-tri-methoxy)-phenyl]-
absent
benzoic acid]
[3-aminomethyl-4-(4-carboxy)-phenyl)-benzoic
absent
acid]
[3-aminomethyl-4-(piperonyl)-benzoic acid]
absent
(3-aminomethyl-4-piperidinyl-benzoic acid)
absent
(3-aminomethyl-4-morpholinyl-benzoic acid)
absent
[3-aminomethyl-4-(N,N-dimethyl)-benzoic
absent
acid]
[3-aminomethyl-4-(2-aminomethylphenyl)-
absent
benzoic acid]
[3-aminomethyl-4-(3-aminomethylphenyl)-
absent
benzoic acid]
[3-aminomethyl-4-(4-aminomethylphenyl)-
absent
benzoic acid]
[3-aminomethyl-4-(4-quinolinyl)-benzoic acid]
absent
[3-aminomethyl-4-(4-quinolinyl)-benzoic acid]
absent
[3-aminomethyl-4-[4-(1-piperazinyl-4-
absent
AlexaFluor 647)phenyl]-benzoic acid]
(N-methyl-3-aminomethyl-benzoic acid)
absent
[N-methyl-3-aminomethyl-4-(4-quinolinyl)-
absent
benzoic acid]
[2-(5-quinolinyl)-Phe]-reduced
betaHomoLys
[3-aminomethyl-4-[4-(1-piperazinyl)-phenyl]-
absent
benzoic acid]
[3-aminomethyl-4-[4-(1-piperazinyl)-phenyl]-
absent
benzoic acid]
[3-aminomethyl-4-[4-(1-piperazinyl)-phenyl]-
absent
benzoic acid]
F
absent
F
absent
F
absent
F
absent
F
absent.
27. The compound of claim 1 , being any one of compounds 1-397, or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, along with the pharmaceutically acceptable carrier.
29. The pharmaceutical composition of claim 28 , formulated for oral delivery.
30. The pharmaceutical composition of claim 28 , formulated for topical delivery.
31. The pharmaceutical composition of claim 28 , formulated for parenteral delivery.
32. A method of treating inflammation or an autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .
33. The method of claim 32 , wherein the inflammation or an autoimmune disease is gastrointestinal.
34. The method of claim 32 , wherein the condition or disease is Inflammatory Bowel Disease (IBD); ulcerative Crohn's disease; Celiac disease; enteropathy associated with seronegative arthropathies microscopic colitis; collagenous colitis; eosinophilic gastroenteritis; radiotherapy; chemotherapy; pouchitis resulting after proctocolectomy and ileoanal anastomosis; gastrointestinal cancer; pancreatitis; insulin-dependent diabetes mellitus; mastitis; cholecystitis; cholangitis; pericholangitis; chronic bronchitis; chronic sinusitis; asthma; primary sclerosing cholangitis; human immunodeficiency virus (HIV) infection in the GI tract; eosinophilic asthma; eosinophilic esophagitis; gastritis; colitis; microscopic colitis; graft versus host disease; colitis associated with radio- or chemo-therapy; colitis associated with disorders of innate immunity; leukocyte adhesion deficiency-1; chronic granulomatous disease; glycogen storage disease type 1; Hermansky-Pudlak syndrome; Chediak-Higashi syndrome; and Wiskott-Aldrich Syndrome; osteoporosis; arthritis; multiple sclerosis; chronic pain; weight gain; or depression.
35. The method of claim 34 , wherein the condition is an inflammatory bowel disease.
36. The method of claim 35 , wherein the inflammatory bowel disease is ulcerative colitis.
37. The method of claim 35 , wherein the inflammatory bowel disease is Crohn's disease.
38. The method of claim 32 , wherein the compound inhibits binding of α4β7 integrin to MAdCAM.
39. The method of claim 32 , wherein the patient is a human.
40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, being selected from the group consisting of compounds 340, 348, 349, and 358.