Bioorganic & Medicinal Chemistry Letters 18 (2008) 375–379
Sulfonamide derivatives of bridgehead substituted
bicyclo[4.2.1]nonanes as c-secretase inhibitors
Tim Sparey,a,* Earl Clarke,b Joanne Hannam,a Timothy Harrison,a Andrew Madin,a
Mark Shearmanb,ꢀ and Bindi Sohala
aDepartment of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Harlow, Essex CM20 2QR, UK
bMolecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Harlow, Essex CM20 2QR, UK
Received 30 August 2007; revised 15 October 2007; accepted 16 October 2007
Available online 22 October 2007
Abstract—Bridgehead substituted derivatives of bicyclo[4.2.1]nonanes were synthesized and shown to be potent inhibitors of
c-secretase. Two related series were synthesized to explore the SARs. More potent compounds were found in the non-benzofused
series compared with the benzofused series. One compound from each series showed good exposure in the hepatic portal vein (HPV)
following oral dosing to rats.
Ó 2007 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is the most common cause
of dementia in the elderly, and with life expectancy
increasing, more patients than ever before will suffer
progressive memory impairment, cognitive deficits
and behavioural problems as a result of AD. Current
therapies are palliative. Approaches towards a disease
modifying therapy include reducing the production of
amyloid-b42 (Ab42) through inhibition of b-secretase
or c-secretase. Such approaches have been of interest
to the pharmaceutical industry, and as a result, a
number of c-secretase inhibitors/modulators are in
clinical development.1
Here we present new c-secretase inhibitors, repre-
sented by C and D which, given the substitution pat-
tern on the respective cores, represent synthetically
challenging types of compounds for which pharmaco-
logical properties are unknown. However, related
compounds have been proposed for use as analgesics
and anti-inflammatories.4 Furthermore, analogues of
such bicyclo[4.2.1]nonanes were prepared to aid in the
re-definition of Bredt’s rule.5
The preparation of bridgehead substituted bicy-
clo[4.2.1]nonanes possessing a quaternary carbon inher-
ent within this structural motif has attracted two main
synthetic strategies (Scheme 1). One involves alkylating
the carbon bearing the most acidic proton prior to cyc-
lisation onto the methylene adjacent to the carbonyl
(method A)5a and the second, generation of the bicyclic
[4.2.1]nonane skeleton through reduction of an enol lac-
tone (method B).5b
Recently we described the use of sulfonamide derivatives
of substituted bicyclo[4.2.1]nonanes and substituted cyc-
lic sulfamides represented by A and B as c-secretase
inhibitors with potential for the treatment of Alzhei-
mer’s disease.2,3
We planned to utilize the bridgehead position as a site
from which a range of groups (R in C and D) could be in-
stalled to build upon the SAR of previously disclosed
compounds2 by exploring the effects of introducing polar,
basic and lipophilic groups on the potency and pharmaco-
kinetic properties of these molecules. Herein we describe
the synthesis of bridgehead substituted benzofused and
non-benzofused bicyclo[4,2,1]nonanes, and derivatisa-
tion to sulfonamides as c-secretase inhibitors.
Keywords: Alzheimer’s disease; c-Secretase inhibitor.
*
Corresponding author at present address: Merck Sharp and Dohme,
Licensing and External Research Europe, Hertford Road, Hoddes-
don EN11 9BU, UK. Tel.: +44 1992 452838; fax: +44 1992 441907;
ꢀ
Present address: Neuroscience Drug Discovery, Merck Research
Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115,
USA.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.057