US 10,683,329 B2Granted

Dual-site BACE1 inhibitors

AssigneeHoffmann-La Roche Inc.

InventorsPer-Ola Freskgard, Eric A. Kitas

Life of this patent

Estimating the term…

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.

Claims15

Dependent claims

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)-NH2 (SEQ ID NO:
96),
ii. Glu-Val-Asn-Sta-Asp-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
97),
iii. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(27-OH-Chol)-NH2 (SEQ ID NO:
100),
iv. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol-27-TFA-ester)-NH2 (SEQ ID NO:
101),
v. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
102),
vi. Glu-Val-Asn-Sta-Val-Ala-Glu-Phe-Lys(Chol)-NH2 (SEQ ID NO:
103),
vii. Glu-Val-Asn-MetSta-Val-Ala-Glu-DPhe-Lys(Chol)-NH2 (SEQ ID NO:
104),
viii. Glu-Val-Asn-Leu*Ala-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
106),
ix. Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ether’)-NH2 (SEQ ID NO:
107),
x. Leu-Pro-Ile-Phe-Tyr-Pro-Tyr-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
108),
xi. Glu-Val-Asn-MetSta-Val-Ala-Glu-Pro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
109), and
xii. Glu-Val-Asn-Leu*Ala-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
110).

21 more elements

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)-NH2 (SEQ ID NO:
3),
Ac-Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(4)-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Cho)-NH2 (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’)-NH2 (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’)-NH2 (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’)-NH2 (SEQ ID NO:
68),
Leu-Ile-Tyr-Phe-Pro-Tyr-Pro-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (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)-NH2 (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’)-NH2 (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’)-NH2 (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’)-NH2 (SEQ ID NO:
67),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys (Cho)-NH2 (SEQ ID NO:
1),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
2),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Asp-Ala-Glu-DPro-Lys(Chol)-NH2 (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)-NH2 (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)-NH2 (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)-NH2 (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)-NH2 (SEQ ID NO:
12),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(3)-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (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)-NH2 (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)-NH2 (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)-NH2(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’)-NH2 (SEQ ID NO:
22),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-NH(CH2)2CO-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (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)-NH2 (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)-NH2 (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)-NH2 (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)-NH2 (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)-NH2 (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)-NH2 (SEQ ID NO:
25),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-PEG(3)-Glu-Val-Asn-MetSta-Val-Ala-Glu-DPhe-Lys(Chol)-NH2 (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)-NH2 (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)-NH2 (SEQ ID NO:
29),
Tyr-DLys-Tyr-Phe-Ile-Leu-Gly-Lys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ether’)-NH2 (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’)-NH2 (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’)-NH2 (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’)-NH2 (SEQ ID NO:
57),
Tyr-Pro-Lys-Phe-Ile-ys-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (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’)-NH2 (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’)-NH2 (SEQ ID NO:
65),
Tyr-Pro-Lys-Phe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-MetSta-Val-Ala-Glu-Pro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
64),
Tyr-Pro-Lys-Phe-Ile-Pro-Leu-Gly-DLys-Gly-lu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
36),
Tyr-Pro-Lys-Phe-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ether’)-NH2 (SEQ ID NO:
44),
Tyr-Pro-Lys-Phe-Ile-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
31),
Tyr-Pro-Lys-Phe-Ile-Ser-Ala-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
70),
Tyr-Pro-Lys-Phe-Lys-Lys-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
47),
Tyr-Pro-Lys-Phc-Lys-Pro-Lcu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
45),
Tyr-Pro-Tyr-DLys-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
58),
Tyr-Pro-Tyr-Lys-Ile-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
50),
Tyr-Pro-Tyr-Phe-DLys-Pro-Lcu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
59),
Tyr-Pro-Tyr-Phe-Ile-DLys-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
60),
Tyr-Pro-Tyr-Phe-Ile-Lys-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
38),
Tyr-Pro-Tyr-Phe-Ile-Lys-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
33),
Tyr-Pro-Tyr-Phe-Ile-Lys-Leu-PEG(4)-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NOS 35 and 96),
Tyr-Pro-Tyr-Phe-Ile-Pro-DLys-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
61),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-DAIa-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
52),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-DLys-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
41),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-DAIa-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
53),
Tyr-Pro-Tyr-Phe-fle-ProLu-Gly-Gly-DLys-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
43),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Lys-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
42),
Tyr-Pro-Tyr-Phe-Ile-Pro-Leu-Gly-Lys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
39),
Tyr-Pro-Tyr-Phe-Ile-Pro-Lcu-Lys-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
40),
Tyr-Pro-Tyr-Phe-Ile-Pro-Lcu-Scr-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
54),
Tyr-Pro-Tyr-Phe-fle-Pro-Lys-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ ID NO:
51),
Tyr-Pro-Tyr-Phe-Lys-Pro-Ala-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol‘ester’)-NH2 (SEQ II) NO:
66),
Tyr-Pro-Tyr-Phe-Lys-Pro-Leu-Gly-DLys-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
37),
Tyr-Pro-Tyr-Phe-Lys-Pro-Leu-Gly-Gly-Gly-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NO:
32), and
Tyr-Pro-Tyr-Phe-Lys-Pro-Leu-PEG(4)-Glu-Val-Asn-Sta-Val-Ala-Glu-DPro-Lys(Chol)-NH2 (SEQ ID NOS 34 and 96),
or a pharmaceutically acceptable salt thereof.

121 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/527,917Filed 25 Nov 2015
Priority: EP 1419532328 Nov 2014
Published: US 2018/0312541 A11 Nov 2018
Granted: 16 Jun 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07K 7/08
Linear peptides containing only normal peptide links: having 12 to 20 amino acids
A61K 38/08
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides having 5 to 11 amino acids
A61K 38/10
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides having 12 to 20 amino acids
A61K 38/55
Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof: protease inhibitors

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US 2018/0312541 A1Pre-grant publication · published 1 Nov 2018
US 10,683,329 B2This patent

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Abstract

Facts

Application

15/527,917Filed 25 Nov 2015

Priority

EP 1419532328 Nov 2014

Published

US 2018/0312541 A11 Nov 2018

Granted

16 Jun 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07K 7/08
Linear peptides containing only normal peptide links: having 12 to 20 amino acids
A61K 38/08
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides having 5 to 11 amino acids
A61K 38/10
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides having 12 to 20 amino acids
A61K 38/55
Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof: protease inhibitors