Bioorganic & Medicinal Chemistry Letters 12 (2002) 2963–2967
Novel Substituted 4-Aminomethylpiperidines as Potent
and Selective Human ꢀ3-Agonists. Part 2:
Arylethanolaminomethylpiperidines
Robert J. Steffan,a,* Mark A. Ashwell,a William R. Solvibile,a Edward Matelan,a
Elwood Largis,b Stella Han,b Jeffery Tilletb and Ruth Mulveyb
aChemical Sciences, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA
bCardiovascular/Metabolic Diseases, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA
Received 13 March 2002; accepted 1 July 2002
Abstract—The synthesis and SAR of a series of b3 adrenoreceptor agonists based on a novel template derived from 4-amino-
methylpiperidine coupled with a common pharmacophore, arylethylamine, is described. This combination led to the identification
of human b3 adrenoreceptor agonists with in vivo activity in a transgenic mouse model.
# 2002 Elsevier Science Ltd. All rights reserved.
Stimulation of b3 adrenoreceptors (AR), expressed on
the cell surface of adipocytes in brown and white adi-
pose tissue, is viewed as a potential treatment for obe-
sity and non-insulin-dependent diabetes mellitus.
Agonists1 of the b3-AR activate an intracellular signal-
ing process in which initiates lipolysis of triglycerides.
The resulting free fatty acids are processed by uncou-
pling protein (UCP) leading to thermogenesis.
Figure 1. The metabolically unstable arylmethoxy link-
age of the aryloxyaminomethylpiperidines was replaced
by a direct bond.
Variations to the aryl moiety and the R-group were
prepared to find the optimal substitutents for b3-AR
agonism while at the same time maintain the good
selectivity over the other b AR’s seen in the earlier aryl-
oxypropanolaminomethylpiperidines.1 The arylethano-
laminomethylpiperidines of Figure 1 were prepared by
reductive amination of a chiral arylethanolamine with a
4-formylpiperidine optimally substituted at the 1 posi-
tion (Scheme 1).
Early efforts by our group in the b3-AR agonist program
at Wyeth identified selective agonists to human b3-AR
which were based on a hybrid template of chiral aryloxy-
propanolamines, common to b-AR antagonists, and 4-
aminomethylpiperidines.2 These compounds were found
to be potent in vitro compounds to CHO cells transfected
with the human b3 adrenoreceptor. They were also selec-
tive over the other b-AR’s but showed low bioavailability
and metabolic cleavage of the aryl ether bond when incu-
bated with human microsomes in the presence of NADH.
The arylethanolamines were prepared as outlined in
Schemes 2–4. The 4-hydroxy-3-methansulfonamido-
phenyl analogue 4 was prepared starting from the opti-
mally substituted acetophenone 1. Chlorination with
benzyltrimethylammonium tetrachloroiodate3 gave
almost exclusively the monochlororinated intermediate
2. Selective reduction with borane in the presence of
(R)-2-methyl-CBS-oxazaborolidine4 in THF gave the
chiral alcohol 3. The chlorine was then converted to the
azide by treatment with sodium azide and sodium
iodide in DMF. Hydrogenation of the azide provided
the chiral phenethanolamine 4.
With the desire to prepare more metabolically stable ana-
logues and improve bioavailability, our recent synthetic
efforts have focused on modifying the aryloxy-
propanolaminomethylpiperidine template to the aryl-
ethanolaminomethylpiperidine template as shown in
The achiral indole 8 was prepared using literature con-
ditions5 from 5, obtained by Friedel–Crafts reaction of
*Corresponding author. Fax:+1-484-865-9398; e-mail: steffar@
wyeth.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00608-X