Recent development of -secretase inhibitors as potential disease-

modifying treatments of Alzheimer’s Disease

Nick Paras, Ana Minatti, and Wenge Zhong

Chemistry Research & Discovery, Amgen Inc., Thousand Oaks, CA 91362

Proposed Contents

1. Introduction
2. The traditional hydroxyethylamine (HEA) derived inhibitors (potency,
permeability and efflux properties, and in vivo efficacy will be
discussed)
3. Novel aminoheterocyclic derived inhibitors
3.1. The aminoheteroaryls
3.2. The aminoquinoxalines
3.3. The cyclic acylguanidines
3.4. The cyclic amindines
3.5. The aminooxazolidines
3.6. The aminothiazolidines
4. Cyclic amine derived inhibitors
4.1. The pyrrolidines
4.2. The piperidines
4.3. The piperizines

5. Others – macrocyclic inhibitors and alternative scaffolds

(publications between now and the time of completion of this review)

6. Summary

(Generic structures and specific examples are listed in the subsequent

pages)
 R3 NH2
H2N
N H2N R4 H2N N O H2N
N F N
N O
N N N N
R2 R1 R2 R1 F R2
R1 R1 Ar N Ar

Wyeth WO2006076284 Astex-Astra/Zeneca Astex-Astra/Zeneca

Wyeth WO2007038271 WO2006041404
Astex-Astra/Zeneca WO2009005470 Wyeth US20060173049
Astex-Astra/Zeneca US20080287462
WO2008076043 WO2008063114

H2N
H2N H2N N O H2N X R1 O
N Y NH2 O
R2 N R3
N O N R3 R3
N N N
R1 H O
R2 R1 R1 R2
R1 R2 R2 N

Schering-Plough Schering-Plough BMS WO2007002214 Roche US20090209529

WO2008103351 Generic: X = O, S, NR3, CR4R5
(7-rings in earlier filings)

O R4 O R4 O
O
H2N R5 H2N N
R1 R1 N S
R1 N R N R
N S N N R N 2 R2 3
2
N H H
N R4 R4
N N N R5
R1 R3 R1 R3 R4 = H, F
R2 R2 R3 R3 Z
A
Merck 2009108550 Merck WO2005097767 Merck WO2007011810 Merck WO2007011810 Pfizer WO2009136350

H H
N N

O O H H
H2N X O N R1 R3 N R1 R1 N R1 N
H2N X X = S only
X = O, S, NR N R2 R2
N X X
R1 R1 Y n = 0, 1, 2
R2 O
n O
R2 R2 Norvatis
Norvatis EP1707202 WO2009106599
Shionogi EP1942105 (2008) Eisai WO2009091016 Norvatis EP1707206

Specific examples:
Schering-Plough WO2009131975

Eli Lilly WO 2009134617

Schering-Plough WO2009131974

Pfizer
WO2009136350
 Data presented on poster
on ACS meeting 2008

IC50 (Ab42-reduction) < 1 nM

BACE1 IC50 = 60 nM
PD data not reported

Wyeth:

Patents

WO2008118379

J. Med. Chem. 2009

(WO2006076284)
 Merck:

Patents

WO2009108550

Boehringer-Ingelheim:
WO2009078932
Patents

WO2009007300

Shionogi:

Patents
~80% reduction in rat
brain A, 10 mpk po
WO2007049532 [EP1942105 (2008)]
WO2008133273
WO2008133274

H2N S
O
N
H N
N N

O
F