Dual-site BACE1 inhibitors

Patent metadata

Field	Value
Publication number	US-10683329-B2
Application number	US-201515527917-A
Country	US
Kind code	B2
Filing date	Nov 25, 2015
Priority date	Nov 28, 2014
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

Provided herein are peptides having dual-site BACE1 inhibitory activity, useful for the treatment of, for example Alzheimer's disease and diabetes. One such peptide is a dual-site BACE1 inhibitor, or a pharmaceutically acceptable salt thereof, binding to both an enzymatic active site and an catalytic domain of the BACE enzyme, and an exosite inhibitory part is connected to an active-site inhibitory part of the dual site BACE1 inhibitor by a linker.

First claim

The invention claimed is:

1. A dual-site BACE1 inhibitor, or a pharmaceutically acceptable salt thereof, binding to both an enzymatic active site and a catalytic domain of the BACE1 enzyme, wherein an exosite inhibitory part (A′) is connected to an active-site inhibitory part (B′) of said dual-site BACE1 inhibitor by a linker (L′), and wherein B′ is selected from the group consisting of:
i. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 96),
ii. Glu-Val-Asn-Sta-Asp-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 97),
iii. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(27-OH-Chol)-NH 2 (SEQ ID NO: 100),
iv. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol-27-TFA-ester)-NH 2 (SEQ ID NO: 101),
v. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 102),
vi. Glu-Val-Asn-Sta-Val-Ala-Glu-Phe-Lys(Chol)-NH 2 (SEQ ID NO: 103),
vii. Glu-Val-Asn-MetSta-Val-Ala-Glu-DPhe-Lys(Chol)-NH 2 (SEQ ID NO: 104),
viii. Glu-Val-Asn-Leu*Ala-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 106),
ix. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ether’)-NH 2 (SEQ ID NO: 107),
x. Leu-Pro-Ile-Phe-Tyr-Pro-Tyr-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 108),
xi. Glu-Val-Asn-MetSta-Val-Ala-Glu-Pro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 109), and
xii. Glu-Val-Asn-Leu*Ala-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 110).

2. The dual-site BACE1 inhibitor according to claim 1 , wherein L′ is selected from the group consisting of:
i. -(Gly) x -, wherein x is 2, 3, 4, 5 or 6 (SEQ ID NO: 111),
ii. —NH(CH 2 ) y CO—, wherein y is 2, 4, 5 or 10,
iii. PEG(3),
iv. PEG(4),
v. —X-Gly-Gly-, wherein X is selected from the group consisting of Ala, DAla, Ser, Lys and DLys,
vi. -Gly-X-Gly-, wherein X is selected from the group consisting of Ala, DAla, Ser, Lys and DLys, and
vii. -Gly-Gly-X—, wherein X is selected from the group consisting of Ala, DAla, Ser, Lys and DLys.

3. The dual-site BACE1 inhibitor according to claim 1 , wherein A′ is selected from the group consisting of:
i. Tyr-Pro-Tyr-Phe-Ile-Pro-Leu- (SEQ ID NO: 71),
ii. Ac-Tyr-Pro-Tyr-Phe-Ile-Pro-Leu- (SEQ ID NO: 72),
iii. Leu-Ile-Tyr-Phe-Pro-Tyr-Pro- (SEQ ID NO: 73),
iv. Tyr-Pro-Lys-Phe-Ile-Pro-Leu- (SEQ ID NO: 74),
v. Tyr-Pro-Tyr-Phe-Lys-Pro-Leu- (SEQ ID NO: 75),
vi. Tyr-Pro-Tyr-Phe-Ile-Lys-Leu- (SEQ ID NO: 76),
vii. Tyr-Pro-Lys-Phe-Lys-Pro-Leu-Gly- (SEQ ID NO: 77),
viii. Tyr-Pro-Lys-Phe-Ile-Lys-Leu- (SEQ ID NO: 78),
ix. Tyr-Pro-Lys-Phe-Lys-Lys-Leu- (SEQ ID NO: 79),
x. Lys-Pro-Tyr-Phe-Ile-Pro-Leu- (SEQ ID NO: 80),
xi. Tyr-Lys-Tyr-Phe-Ile-Pro-Leu- (SEQ ID NO: 81),
xii. Tyr-Pro-Tyr-Lys-Ile-Pro-Leu- (SEQ ID NO: 82),
xiii. Tyr-Pro-Tyr-Phe-Ile-Pro-Lys- (SEQ ID NO: 83),
xiv. DLys-Pro-Tyr-Phe-Ile-Pro-Leu- (SEQ ID NO: 84),
xv. Tyr-DLys-Tyr-Phe-Ile-Pro-Leu- (SEQ ID NO: 85),
xvi. Tyr-Pro-DLys-Phe-Ile-Pro-Leu- (SEQ ID NO: 86),
xvii. Tyr-Pro-Tyr-DLys-Ile-Pro-Leu- (SEQ ID NO: 87),
xviii. Tyr-Pro-Tyr-Phe-DLys-Pro-Leu- (SEQ ID NO: 88),
xix. Tyr-Pro-Tyr-Phe-Ile-DLys-Leu- (SEQ ID NO: 89),
xx. Tyr-Pro-Tyr-Phe-Ile-Pro-DLys- (SEQ ID NO: 90),
xxi. Lys,
xxii. DLys,
xxiii. Tyr-Pro-Tyr-Phe-Lys-Pro-Ala- (SEQ ID NO: 91),
xxiv. Thr-Phe-Lys-Pro-Ala-Asn-Gly- (SEQ ID NO: 92),
xxv. Gly-Ala-Arg-Phe-Ile-Pro-Ala- (SEQ ID NO: 93),
xxvi. Tyr-Pro-Lys-Phe-Ile-Pro-Ala- (SEQ ID NO: 94), and
xxvii. Tyr-Pro-Lys-Phe-Ile-Ser-Ala- (SEQ ID NO: 95).

4. A dual-site BACE1 inhibitor, selected from the group consisting of:
Ac-Tyr-Pro-Tyr-Phe-Ile-Pro-Lcu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 3),
Ac-Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(4)-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Cho)-NH 2 (SEQ ID NOS 15 and 96),
DLys-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 55),
DLys-Gly-DLys-Gly-Leu-Pro-Ile-Phe-Tyr-Pro-Tyr-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 63),
Gly-Ala-Arg-Phe-Ile-Pro-Ala-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 68),
Leu-Ile-Tyr-Phe-Pro-Tyr-Pro-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 16),
Leu-Ile-Tyr-Phe-Pwo-Tyr-Pro-Gly-Gly-Gily-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 17),
Lys-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 48),
Lys-Gly-DLys-Gly-Leu-Pro-Ile-Phe-Tyr-Pro-Tyr-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 62),
Thr-Phe-Lys-Pro-Ala-Asn-Gly-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 67),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys (Cho)-NH 2 (SEQ ID NO: 1),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 2),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Asp-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 4),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 5),
Tyr-Pro-Tyr-Ph-Ile-Pro-Lu-Gly-Gly-Gly-Gly-Glu-Val-Asn-Sta-Asp-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 6),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 7),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 12),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(3)-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NOS 13 and 96),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(4)-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NOS 14 and 96),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(27-OH-Chol)-NH 2 (SEQ ID NO: 20),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol-27-TFA-ester)-NH 2 (SEQ ID NO: 21),
Tyr-Pro-Ty-Phe-Ile-Pro-Leu-ly-Ly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-(Chol-27-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 22),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-NH(CH2)2CO-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NOS 8 and 96),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-NH(CH2)4CO-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NOS 9 and 96),
Tyr-Pro-Tyr-Phe-Ile-r-Leu-N H(CH2)5CO-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NOS 10 and 96),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-NH(CH2)10CO-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NOS 11 and 96),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 23),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Gly-Glu-Val-Asn-MetSta-Val-Ala-Glu-DPhe-Lys(Chol)-NH 2 (SEQ ID NO: 24),
Tyr-Pro-Tyr-Phe-fle-Pro-Leu-Gly-Gly-Gly-Gly-Gly-Glu-Val-Asn-MetSta-Val-Ala-Glu-DPhe-Lys(Chol)-NH 2 (SEQ ID NO: 25),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(3)-Glu-Val-Asn-MetSta-Val-Ala-Glu-DPhe-Lys(Chol)-NH 2 (SEQ ID NOS 26 and 104),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(4)-Glu-Val-Asn-MetSta-Val-Ala-Glu-DPhe-Lys(Cho)-NH 2 (SEQ ID NOS 27 and 104),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Leu*Ala-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 29),
Tyr-DLys-Tyr-Phe-Ile-Leu-Gly-Lys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ether’)-NH 2 (SEQ ID NO: 30),
Tyr-Lys-Tyr-Pe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 56),
Tyr-Pro-DLy-Pe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 49),
Tyr-Lys-Tyr-Pe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 57),
Tyr-Pro-Lys-Phe-Ile-ys-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH 2 (SEQ ID NO: 46),
Tyr-Pro-Lys-Phe-Ile-Pro-Ala-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 69),
Tyr-Pro-Lys-Phe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Leu*Ala-Ala-Glu-DPro-Lys(Chol‘ester’)-NH 2 (SEQ ID NO: 65),
Tyr-Pro-Lys-Phe-Ile-Pro-Leu-Gly-D

Assignees

• Hoffmann La Roche

Inventors

• Freskgard Per-Ola
• Kitas Eric A

Classifications

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/55

  Protease inhibitors · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title