Bioorganic & Medicinal Chemistry Letters
Discovery of 2-methylpyridine-based biaryl amides as
modulators for the treatment of Alzheimer’s disease
c-secretase
a
a
a
a
a
Jian Jeffrey Chen a, , Wenyuan Qian , Kaustav Biswas , Chester Yuan , Albert Amegadzie , Qingyian Liu ,
Thomas Nixey a, Joe Zhu a, Mqhele Ncube a, Robert M. Rzasa a, Frank Chavez Jr. a, Ning Chen a,
Frenel DeMorin a, Shannon Rumfelt a, Christopher M. Tegley a, Jennifer R. Allen a, Stephen Hitchcock a,
Randy Hungate a, Michael D. Bartberger a, Leeanne Zalameda a, Yichin Liu a, John D. McCarter a,
Jianhua Zhang b, Li Zhu b, Safura Babu-Khan b, Yi Luo b, Jodi Bradley b, Paul H. Wen b, Darren L. Reid c,
Frank Koegler d, Charles Dean Jr. d, Dean Hickman e, Tiffany L. Correll f, Toni Williamson b,d, Stephen Wood b
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a Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
b Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
c Pharmaceutical R&D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
d Department of Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
e Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
f Analytical Research & Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
c
-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer’s disease.
They selectively lower pathogenic Ab42 levels by shifting the enzyme cleavage sites without inhibiting
-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the
Received 9 August 2013
Revised 12 September 2013
Accepted 13 September 2013
Available online 29 September 2013
c
enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization
studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Ab42 levels
in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimiza-
tion of 25 to improve cellular potency is described.
Keywords:
c
c
-Secretase modulator (GSM)
-Secretase inhibitor (GSI)
Ó 2013 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD)
Amyloid b-protein (Ab)
Methylpyridine
Amide as sulfonamide replacement
Alzheimer’s disease (AD) is the most common dementia affecting
more than 5 million patients in the US. According to the amyloid
hypothesis,1–3 aggregation of the amyloid b-protein (Ab), particu-
larly its 42-residue variant (Ab42), plays a direct role in the
pathogenesis of AD, and therefore agents that could lower Ab levels
in the brain should be a useful treatment for AD. Ab is generated
through sequential cleavage of amyloid precursor protein (APP) by
lowering pathogenic Ab42 levels by shifting the enzymatic cleavage
sites to generate shorter and less aggregation-prone forms of the Ab
peptide such as Ab37 and Ab38.10–19 The processing of other
c-
secretase substrates such as Notch does not appear to be affected
by the -secretase modulators (GSMs), thus avoiding side effects
c
associated with GSIs. Herein, we describe the discovery of an orally
efficacious 2-methylpyridine-based amide GSM 2520 through lead
optimization of a high throughput screen (HTS) lead sulfonamide 1.
At the start of our program only a few nonsteroidal anti-inflam-
matory drugs (NSAID)-derived carboxylic acids and imidazole-
based heterocycles represented by compounds 2 and 3 were
b-secretase (BACE) and
become popular AD drug discovery targets over the last decade
c
-secretase (GS).4 These enzymes have
and several inhibitors of each enzyme have been advanced into clin-
ical trials.5–7 However, development of
c
-secretase inhibitors (GSIs)
are challenging, largely due to mechanism-based toxicity associated
with inhibition of other
-secretase substrates such as Notch.8,9 An
disclosed chemotypes of c
-secretase modulators (GSMs).11 Both 2
c
and 3 have the same imidazole phenyl moiety that was subse-
alternative approach, called
c-secretase modulation, involves
quently used in a wide variety of GSMs.11
We used a high-throughput homogeneous time-resolved fluo-
rescence (HTRF) assay to screen for inhibitors of Ab42 production
in Human Embryonic Kidney 293 cells (HEK293 cells) with stable
expression of guinea pig Swedish mutant SFV-APP695sw. A cell
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Corresponding author. Tel.: +1 805 447 8498; fax: +1 805 480 1337.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.