US2020040037A1PendingUtilityA1
Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
Assignee: PROTAGONIST THERAPEUTICS INCPriority: Jul 12, 2018Filed: Jul 12, 2019Published: Feb 6, 2020
Est. expiryJul 12, 2038(~11.9 yrs left)· nominal 20-yr term from priority
C07K 7/02C07K 7/08C07K 7/56A61K 38/00
56
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Claims
Abstract
The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.
Claims
exact text as granted — not AI-modified1 . A peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises an amino acid sequence of Formula (I):
X7-X8-X9-X10-X11 (I)
wherein X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen or Pen(sulfoxide); X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and provided that i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; ii) X7 is other than 5-F substituted Trp; and iii) when X7 is unsubstituted Trp, or Trp substituted with 1-Me, 5-OH or 6-Cl; then X9 is other than Cys; and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.
2 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (II):
X4-X5-X6-X7-X8-X9-X10-X11 (II)
wherein X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide), wherein if X4 is Abu then X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide), and wherein if X9 is Abu, then X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen or Pen(sulfoxide); X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy; wherein the peptide inhibitor is cyclized via a bond between X4 and X9, and provided that
i) at least one of X7 and X11 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
ii) X7 is other than 5-F substituted Trp; and
iii) when X7 is unsubstituted Trp, or Trp substituted with 1-Me, 5-OH or 6-Cl; then X9 is other than Cys;
and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.
3 - 18 . (canceled)
19 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IIa) (IIb), or (IIc):
(IIa)
Pen-X5-X6-X7-X8-Pen-X10-X11,
(IIb)
Abu-X5-X6-X7-X8-Cys-X10-X11,
or
(IIc)
Abu-X5-X6-X7-X8-Pen-X10-X11,
wherein
X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys;
X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val;
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp;
X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or the peptide inhibitor is cyclized via a Abu-Cys or Abu-Pen thioether bond.
20 - 22 . (canceled)
23 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IIIa), (IIIb), (IIIc), or (IIId):
(IIIa)
Pen-Asn-X6-X7-X8-Pen-X10-X11,
(IIIb)
Pen-Gln-X6-X7-X8-Pen-X10-X11,
(IIIc)
Abu-Asn-X6-X7-X8-Cys-X10-X11,
or
(IIId)
Abu-Gln-X6-X7-X8-Pen-X10-X11,
wherein
X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val;
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp;
X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
24 . (canceled)
25 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IVa), (IVb), (IVc), or (IVd):
(IVa)
Pen-Asn-Thr-X7-X8-Pen-X10-X11,
(IVb)
Pen-Gln-Thr-X7-X8-Pen-X10-X11,
(IVc),
Abu-Asn-Thr-X7-X8-Cys-X10-X11,
or
(IVd)
Abu-Gln-Thr-X7-X8-Pen-X10-X11,
wherein
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp;
X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
26 - 27 . (canceled)
28 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Va), (Vb), (Vc), or (Vd):
(Va)
Pen-Asn-Thr-X7-Gln-Pen-X10-X11,
(Vb)
Pen-Gln-Thr-X7-Gln-Pen-X10-X11,
(Vc)
Abu-Asn-Thr-X7-Gln-Cys-X10-X11,
or
(Vd)
Abu-Gln-Thr-X7-Gln-Pen-X10-X11
wherein
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
29 - 30 . (canceled)
31 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (VIa), (VIb), (VIc), or (VId):
(VIa)
Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11,
(VIb)
Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11,
(VIc)
Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11,
or
(VId)
Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11
wherein
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
[F(4-2ae)] is Phe[4-(2-aminoethoxy)]; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
32 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (II′):
X7-X8-X9-X10-X11-X12-X13-X14-X15 (II′)
and wherein
X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, or cyclohexylAla, Lys, or Aib;
X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys; or
X13 is Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), wherein Y2 is an amino acid;
X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); and
X15 is Asn, Leu, Aib, (D)Leu, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), (D)Lys, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent.
33 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 32 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (VIIa), (VIIb), or (VIIc):
(VIIa)
Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-
X14-X15,
(VIIb)
Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-
X14-X15,
or
(VIIc)
Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-
X14-X15
wherein
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X12-X15 are as described in claim 32 ; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
34 - 40 . (canceled)
41 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 32 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (VIIIa), (VIIIb) or (VIIIc):
(VIIIa)
Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-
K(Ac)-X14-X15,
(VIIIb)
Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-
K(Ac)-X14-X15,
or
(VIIIc)
Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-
K(Ac)-X14-X15
wherein
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X14, and X15 are as described in claim 32 ; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
42 - 43 . (canceled)
44 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 32 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IXa), (IXb), or (IXc):
(IXa)
Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-
K(Ac)-Asn-Asn,
(IXb)
Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-
K(Ac)-Asn-Asn,
or
(IXc)
Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-
K(Ac)-Asn-Asn
wherein
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
45 - 46 . (canceled)
47 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 32 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Xa), (Xb), (Xc), (Xd), (Xe), or (Xf):
(Xa)
Pen-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-
K(Ac)-Asn-Asn,
(Xb)
Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-
K(Ac)-Asn-Asn,
(Xc)
Abu-Asn-Thr-W′-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-
K(Ac)-Asn-Asn,
(Xd)
Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-W′-aMeLeu-
K(Ac)-Asn-Asn,
(Xe)
Abu-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-
K(Ac)-Asn-Asn,
or
(Xf)
Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-
K(Ac)-Asn-Asn
wherein
X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;
X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with halo, alkyl, haloalkyl, hydroxy, or alkoxy;
and W′ is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
48 - 51 . (canceled)
52 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (XIa), (XIb), (XIc), (XId), (XIe), or (XIf):
(XIa)
(SEQ ID NO: 100)
Pen-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-[2-Nal]-
aMeLeu-K(Ac)-Asn-Asn,
(XIb)
(SEQ ID NO: 101)
Pen-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-
K(Ac)-Asn-Asn,
(XIc)
(SEQ ID NO: 102)
Abu-Asn-Thr-W′-Gln-Cys-[F(4-2ae)]-[2-Nal]-
aMeLeu-K(Ac)-Asn-Asn,
(XId)
(SEQ ID NO: 103)
Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W′-aMeLeu-
K(Ac)-Asn-Asn,
(XIe)
(SEQ ID NO: 104)
Abu-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-[2-Nal]-
aMeLeu-K(Ac)-Asn-Asn,
or
(XIf)
(SEQ ID NO: 105)
Abu-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-
K(Ac)-Asn-Asn,
wherein W′ is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.
53 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide inhibitor comprises the structure of Formula (Z):
R 1 —X—R 2 (Z)
or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a bond, hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl-C1-6alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; X is the amino acid sequence of Formula (I), or an amino acid sequence set forth in any of Table E1, E2, or E3; and R 2 is OH or NH 2 .
54 . (canceled)
55 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 53 , wherein R 1 is H or Ac.
56 - 62 . (canceled)
63 . A peptide inhibitor of an interleukin-23 receptor, wherein the peptide inhibitor is any one of the amino acid sequence listed below; or a pharmaceutically acceptable salt or solvate thereof:
(SEQ ID NO: 6)
Ac-[Pen]-NT-[W(7-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-
[Lys(Ac)]-NN-NH 2 ;
(SEQ ID NO: 201)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-N-
[bA]-NH 2 ;
(SEQ ID NO: 227)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-
N-[bA]-NH 2 ;
(SEQ ID NO: 242)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[bA]-NH 2 ;
(SEQ ID NO: 245)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 248)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-H-NH 2 ;
(SEQ ID NO: 249)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[Cit]-NH 2 ;
(SEQ ID NO: 251)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Val]-NH 2 ;
(SEQ ID NO: 252)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Lys]-NH 2 ;
(SEQ ID NO: 256)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[(D)Arg]-NH 2 ;
(SEQ ID NO: 258)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Phe]-NH 2 ;
(SEQ ID NO: 259)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[(D)Tyl]-NH 2 ;
(SEQ ID NO: 260)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-S-NH 2 ;
(SEQ ID NO: 261)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[(D)Ser]-NH 2 ;
(SEQ ID NO: 263)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[(D)Thi]-NH 2 ;
(SEQ ID NO: 264)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[Aib]-NH 2 ;
(SEQ ID NO: 265)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
[N-MeAla]-NH 2 ;
(SEQ ID NO: 267)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-
[bA]-NH 2 ;
(SEQ ID NO: 274)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Achc]-[Lys(Ac)]-N-
[bA]-NH 2 ;
(SEQ ID NO: 276)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[DiethylGly]-[Lys(Ac)]-
N-[bA]-NH 2 ;
(SEQ ID NO: 277)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acbc]-[Lys(Ac)]-N-
[bA]-NH 2 ;
(SEQ ID NO: 278)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeOrn]-[Lys(Ac)]-
N-[bA]-NH 2 ;
(SEQ ID NO: 284)
Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 285)
Ac-[Pen]-N-T-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 320)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;;
or
(SEQ ID NO: 322)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Aib)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 4)
Ac-[Pen]-NT-[W(4-OMe)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-
[Lys(Ac)]-NN-NH 2 ;
(SEQ ID NO: 5)
Ac-[Pen]-NT-[W(6-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-
[Lys(Ac)]-NN-NH 2 ;
(SEQ ID NO: 13)
Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(6-Cl)-[α-MeLeu]-[Lys(Ac)]-NN-
NH 2 ;
(SEQ ID NO: 16)
Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(6-Me)-[α-MeLeu]-[Lys(Ac)]-NN-
NH 2 ;
(SEQ ID NO: 22)
Ac-[Pen]-NTW-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-W(5-Br)-[α-MeLeu]-[Lys(Ac)]-NN-
NH 2 ;
(SEQ ID NO: 202)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-
[bA]-NH 2 ;
(SEQ ID NO: 203)
Ac-[(D)Arg]-Abu-Q-T-[W(7-Me)]-Q-C-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[bA]-
NH 2 ;
(SEQ ID NO: 204)
Ac-Abu-Q-T-[W(7-Me)]-Q-C-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[bA]-NH 2 ;
(SEQ ID NO: 205)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-G-
[bA]-NH 2 ;
(SEQ ID NO: 207)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-A-
[bA]-NH 2 ;
(SEQ ID NO: 208)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-L-
[bA]-NH 2 ;
(SEQ ID NO: 209)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-
[(D)Ala]-[bA]-NH 2 ;
(SEQ ID NO: 214)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-H-
[bA]-NH 2 ;
(SEQ ID NO: 215)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-
[(D)His]-[bA]-NH 2 ;
(SEQ ID NO: 217)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-T-
[bA]-NH 2 ;
(SEQ ID NO: 221)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-S-
[bA]-NH 2 ;
(SEQ ID NO: 222)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-[Lys(Ac)]-
[(D)Ser]-[bA]-NH 2 ;
(SEQ ID NO: 231)
Ac-[Pen]-NT-[W(4-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-
[bA]-NH 2 ;
(SEQ ID NO: 232)
Ac-[Pen]-NT-[W(1-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-
[bA]-NH 2 ;
(SEQ ID NO: 234)
Ac-[Pen]-NT-[W(7-Me)]-[a-MeLys]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLeu]-
[Lys(Ac)]-N-[bA]-NH 2 ;
(SEQ ID NO: 235)
Ac-[Pen]-NT-[W(7-Me)]-[a-MeLeu]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[bA]-NH 2 ;
(SEQ ID NO: 236)
Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Aib]-N-
[bA]-NH 2 ;
(SEQ ID NO: 237)
Ac-[Pen]-Q-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[bA]-NH 2 ;
(SEQ ID NO: 238)
Ac-[Pen]-[Cit]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[bA]-NH 2 ;
(SEQ ID NO: 239)
Ac-[Pen]-[Lys(Ac)]-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[bA]-NH 2 ;
(SEQ ID NO: 243)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-R-NH 2 ;
(SEQ ID NO: 244)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-L-NH 2 ;
(SEQ ID NO: 246)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[NMeArg]-NH 2 ;
(SEQ ID NO: 247)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[bhPhe]-NH 2 ;
(SEQ ID NO: 250)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-V-NH 2 ;
(SEQ ID NO: 253)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-P-NH 2 ;
(SEQ ID NO: 254)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Pro]-NH 2 ;
(SEQ ID NO: 255)
Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-I-NH 2 ;
(SEQ ID NO: 257)
Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[(D)Phe]-NH 2 ;
(SEQ ID NO: 268)
Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-[bA]-[bA]-NH 2 ;
(SEQ ID NO: 269)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
L-[bA]-NH 2 ;
(SEQ ID NO: 270)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-[bA]-[bA]-NH 2 ;
(SEQ ID NO: 271)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-S-[bA]-NH 2 ;
(SEQ ID NO: 272)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-H-[bA]-NH 2 ;
(SEQ ID NO: 273)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-E-
[bA]-[bA]-NH 2 ;
(SEQ ID NO: 275)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Spiral_Pip]-[Lys(Ac)]-
N-[bA]-NH 2 ;
(SEQ ID NO: 279)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Cit]-[bA]-
[bA]-NH 2 ;
(SEQ ID NO: 282)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-E-N-[bA]-
NH 2 ;
(SEQ ID NO: 283)
Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[W(1-Me)]-[a-MeLys]-
[Lys(Ac)]-N-[bA]-NH 2 ;
(SEQ ID NO: 286)
Ac-[Pen]-N-T-[W(7-i-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 288)
Ac-[Pen]-N-T-[W(7-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 289)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[2-Nal]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-
[(D)Leu]-NH 2 ;
(SEQ ID NO: 290)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-H-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-
NH 2 ;
(SEQ ID NO: 297)
Ac-[Pen]-N-T-[W(7-OMe)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-
N-[(D)Lys]-NH 2 ;
(SEQ ID NO: 299)
Ac-[Pen]-N-T-[W(7-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Lys]-NH 2 ;
(SEQ ID NO: 314)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ala)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 315)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(IVA)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 316)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(cyclohexanoic)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-
MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 321)
Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-
[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 323)
Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-
MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH 2 ;
(SEQ ID NO: 325)
Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-
MeLys]-[Lys(Ac)]-N-[(D)Leu]-NH 2 ;
(SEQ ID NO: 27)
Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH 2 ;
(SEQ ID NO: 28)
Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-NH 2 ;
(SEQ ID NO: 29)
Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-
NN-NH 2 ;
or
(SEQ ID NO: 30)
Ac-[Abu]-QT-[W(7-Me)]-QC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NN-NH 2 ;
and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or via an Abu-C thioether bond;
or a pharmaceutically acceptable salt or solvate thereof.
64 .- 65 . (canceled)
66 . A peptide inhibitor of an interleukin-23 receptor, wherein the peptide inhibitor is an amino acid sequence set forth in any of Table E1, E2, or E3; or a pharmaceutically acceptable salt or solvate thereof.
67 . (canceled)
68 . The peptide inhibitor of claim 1 , wherein the peptide is:
and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond;
or a pharmaceutically acceptable salt or solvate thereof.
69 - 74 . (canceled)
75 . A pharmaceutical composition comprising the peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , and a pharmaceutically acceptable carrier, excipient, or diluent.
76 - 77 . (canceled)
78 . A method for treating an Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft versus host disease in a subject, comprising providing to the subject an effective amount of the peptide inhibitor or peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of claim 1 , or the pharmaceutical composition of claim 75 .
79 - 81 . (canceled)Join the waitlist — get patent alerts
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