Discovery of benzamides as potent human β3 adrenergic receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2015.11.030

The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human β₃-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered e

Full text of DOI:10.1016/j.bmcl.2015.11.030

Bioorganic & Medicinal Chemistry Letters 26 (2016) 55–59
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of benzamides as potent human b3 adrenergic receptor
agonists
b
a
b
a
a
a
Cheng Zhu a, , Nam F. Kar , Bing Li , Melissa Costa , Karen H. Dingley , Jerry Di Salvo , Sookhee N. Ha ,
Amanda L. Hurley b, Xiaofang Li b, Randy R. Miller a, Gino M. Salituro b, Mary Struthers a, Ann E. Weber a,
Jeffrey J. Hale b, Scott D. Edmondson a
⇑
a Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States
b Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse
amide) as potent and selective human b3-adrenergic receptor agonist. Based on conformationally
restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was syn-
thesized. From library synthesis and further optimization efforts, several structurally diverse reverse
amides such as 24c and 24i were found to have excellent human b3-adrenergic potency and good selec-
tivity over the b1 and b2 receptors. In addition to human b1, b2, b3 and hERG data, PK of selected com-
pounds will be described.
Received 9 October 2015
Revised 6 November 2015
Accepted 9 November 2015
Available online 11 November 2015
Keywords:
b3 adrenergic receptor agonist
Reverse amide
Ó 2015 Elsevier Ltd. All rights reserved.
Pyrrolidine scaffold
Bioisostere
Overactive bladder
The b3-adrenergic receptor (b3-AR) is present primarily in
brown and white adipose tissue and is involved in the regulation
of lipolysis and thermogenesis.1,2 b3-Adrenergic receptor agonists
can cause weight loss in rodents and dogs due to increased lipoly-
sis and thermogenesis.2 Consequently, b3-adrenergic receptor ago-
nists were studied extensively in the 1980s and 1990s for the
treatment of obesity and type 2 diabetes.3 Several compounds have
entered clinic trials, however, despite the promising effects in pre-
clinical species (especially in rodents), b3-adrenergic receptor ago-
nists have so far failed to show weight loss efficacy in humans.
Further studies have shown that the b3-adrenergic receptor is
not only expressed in adipose tissue but also in bladder detrusor
muscle of various mammals.4,5 It has been demonstrated that
b3-AR agonists relax bladder detrusor smooth muscle.4b,6
Additionally, b3-AR agonists increase bladder capacity.7 As a result,
the b3-adrenergic receptor has become an attractive target for the
treatment of overactive bladder (OAB),8,9 with its symptoms of
urgency, with or without urgency incontinence, usually with fre-
quency and nocturia. Due to an aging population, more and more
people are affected by this disorder. The renewed research and
development activities on b3-AR agonists have led several com-
pounds to the clinic for the treatment of overactive bladder.
Recently, mirabegron (1, YM-178, Fig. 1) has obtained regulatory
approval for the treatment of OAB.10,11
Most b3-AR agonists have a linear ethanolamine moiety as
shown in mirabegron’s structure. We have recently reported a
novel pyrrolidine scaffold which constrains the acyclic conforma-
tion (Fig. 2).12a This unique modification maintains the human
b3-AR potency while improving metabolic stability. Compound 2
demonstrated potent human b3-AR agonist activity and
selectivity over the b1 and b2 receptors. Further optimization of
both the left-hand side aromatic and the right-hand side
heterocycle regions led to compounds such as 3, which has a
good balance of potency, selectivity and reduced intrinsic
clearance compared to our initial series.12b In rats, compound 3
demonstrated reduced bladder pressure dose-dependently
following intravenous dosing.12b
Based on the pyrrolidine scaffold, we have discovered vibegron,
a potent and selective b3 adrenergic receptor agonist (4, MK-4618,
Fig. 3).13 Vibegron addresses several liabilities associated with our
earlier clinic candidate MK-0634 (compound 5, Fig. 3),14 and it is
currently in late stage human clinical trials for the treatment of
overactive bladder.
Mirabegron, vibegron and MK-0634 are aniline-derived amides
or sulfonamide. Although no issue associated with the aniline
structure was found during the discovery and development of
vibegron, the back-up program focused on the identification of
⇑
Corresponding author. Tel.: +1 908 740 4597.
E-mail address: cheng.zhu@merck.com (C. Zhu).
http://dx.doi.org/10.1016/j.bmcl.2015.11.030
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

56
C. Zhu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 55–59
OH
cyclize via conjugate addition across the double bond. Then,
NH2
S
H
N
in situ protection of the pyrrolidine ring followed by separation
of the stereoisomers afforded the desired cis isomer 13 (32%) along
with the trans isomers (50%). Finally hydrogenation of the nitro
group gave the pyrrolidine aniline intermediate 14.18
O
N
N
H
1
Figure 1. Structure of mirabegron.
With this alternate synthesis of pyrrolidine aniline 14 success-
fully developed, we explored a similar approach for the pyrrolidine
benzoic acid precursor. Our first generation pyrrolidine benzoic
acid core synthesis is described in Scheme 2. A Wittig reaction of
(4-(methoxycarbonyl)benzyl)-triphenyl phosphonium chloride
with intermediate 10 from the above pyrrolidine aniline synthesis
(Scheme 1) afforded alkene 15. Simultaneous deprotection of the
acetonide and the Boc group gave amino styrene 16 as an HCl salt.
However, unlike the corresponding nitro compound 12 which
cyclized via conjugate addition at room temperature, amino styr-
ene 16 failed to cyclize to form the pyrrolidine under a variety of
reaction conditions. The double bond in ester 16 is apparently
not electron deficient enough to allow the conjugate addition to
occur. Thus a different synthetic approach was explored. After
hydroxy and amine protection, compound 17 was oxidized to
epoxide 18. Palladium catalyzed rearrangement gave ketone 19.
Hydrogenation of 19 accomplished several tandem reactions in a
similar fashion as was reported for an early synthesis of the pyrro-
lidine aniline.12 Thus deprotection of the Cbz group, cyclic imine
formation followed by imine reduction afforded pyrrolidine 20
with excellent cis selectivity, all in a single pot. The amine group
was then protected as a BOC derivative. Finally, TBS deprotection
followed by ester hydrolysis afforded pyrrolidine benzoic acid
intermediate 22.
OH
OH
NH2
S
H
N
H
N
O
O
N
N
N
N
N
H
N
H
3
2
hEC50: 3.7 nM (84% Act)
hEC50: 0.98 nM (99% Act)
Figure 2. Pyrrolidine scaffold.
OH
H
N
OH
H
N
O
O
N
NH
SO2
N
N
N
H
N
F3C
4
S
Vibegron (MK-4618)
5
Compound (MK-0634)
Figure 3. Structures of Merck b3-AR agonists that have entered the clinic.
structurally distinct b3-AR agonist scaffolds to address any unfore-
seen issues that may encountered during continued development
of this lead compound. One successful approach was based on a
reverse amide (benzamide) scaffold.15,16 As we had already
demonstrated that the pyrrolidine scaffold provides several advan-
tages over the linear ethanolamine in the aniline amide series,12a
we elected to leverage this conformationally constrained
pyrrolidine core structural feature. First, an efficient synthesis of
the key intermediate pyrrolidine benzoic acid core had to be
developed.
During the course of the discovery of vibegron, several synthe-
ses of the pyrrolidine aniline core were developed. In addition to
the two published medicinal chemistry syntheses,12 there was
another synthesis which is illustrated in Scheme 1. Commercially
available (1R,2R)-2-amino-1-phenyl-1,3-propanediol 6 was first
selectively protected to give 7.17 Swern oxidation converted the
primary hydroxy to the aldehyde 8. A Wittig reaction with
(triphenyl phosphanylidene) acetaldehyde afforded unsaturated
aldehyde 9. The carbon–carbon double bond was then reduced to
saturated aldehyde 10 which underwent a second Wittig reaction
with (4-nitrobenzyl) triphenyl phosphonium bromide to give
alkene 11 as a cis/trans mixture. After deprotection and subsequent
removal of the solvent, neutralization of the HCl salt 12 with
Hünig’s base in DMF enabled the free amine to spontaneously
With the key intermediate 22 in hand, the synthesis of the final
benzamide was straightforward as illustrated in Scheme 3. Amide
bond coupling with EDC followed by Boc deprotection afforded a
variety of benzamide analogs.
We first synthesized several analogs based on previous aniline
amide SAR results. One such compound was 24a, a direct reverse
amide analog of compound 2 (EC50 = 0.98 nM, Fig. 2). We were
pleased to find that it had good human b3 potency (EC50 = 24 nM)
and maintained selectivity over human b1, b2 receptors and the
human Ether-à-go-go Related Gene (hERG) potassium channel
(Table 1). However, it was about 20 times less potent than aniline
amide 2. We envisioned that SAR for the right hand side of the
molecule in the benzamide series could be different from that of
the anilides. Consequently, the best right hand side acid piece in
the aniline amide series may not necessarily be the best amine
piece for the reverse amide (benzamide). Through a library
synthesis effort in which the amine selection was not limited by
the aniline amide SAR, many structurally diverse benzamides were
explored. Among them, piperidine amide 24b with a simple
ester substitution was found to have moderate b3 activity
(EC50 = 63 nM), providing an excellent starting point for new target
design. The introduction of
a
spiro substituted lactone 24c
O
O
O
OH
O
O
d
NO2
a, b
c
e
f
NBoc
O
NBoc
O
NBoc
O
NBoc
NH2
OH
NBoc
OH
8
9
10
7
11
6
OH
OH
OH
Boc
Boc
N
NO2
N
g
h
NH2HCl
i
NO2
NH2
14
12
13
Scheme 1. Synthesis of the pyrrolidine aniline core. Reagents and conditions: (a) acetone/toluene, reflux; (b) Boc2O, THF, rt, 91% over two steps; (c) (COCl)2, DMSO, Et3N,
CH2Cl2; (d) Ph3PCHCHO, CH2Cl2, iPr2NEt, rt, 68% over two steps; (e) H2, Pd/C, acetone, 60%; (f) (4-nitrobenzyl)triphenylphosphonium bromide, Et3N, CH2Cl2, rt, 58%; (g) HCl,
i
MeOH, 40 °C; (h) Pr2NEt, DMF, rt overnight, then Boc2O, 32% desired cis over two steps; (i) H2, Pd/C, EtOH, rt, 95%.

C. Zhu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 55–59
57
O
OH
OTBS
NHCbz
O
CO2Me
CO2Me
CO2Me
NBoc
NH2HCl
NBoc
O
e
a
b
c, d
15
16
17
10
OTBS
OTBS
OTBS
OTBS
H
N
Boc
N
NHCbz
CO2Me
CO2Me
NHCbz
f
g
h
O
O
CO2Me
CO2Me
20
21
19
18
OH
Boc
N
i. j
CO2H
22
Scheme 2. Synthesis of the pyrrolidine benzoic acid core. Reagents and conditions: (a) (4-(methoxycarbonyl)benzyl)triphenylphosphonium chloride, NaOtBu DMSO, rt, 77%;
(b) HCl, MeOH, rt, 68%; (c) TBSCl, iPr2NEt, DMF, rt; (d), CbzCl, iPr2NEt, CH2Cl2, À78 °C to rt, 76% over two steps; (e) MCPBA, CH2Cl2, rt, 95%; (f) Pd(OAc)2, PPh3/PBu3, EtOH/THF,
reflux, 81%; (g) H2, Pd/C, ethanol, rt; (h) Boc2O, THF, rt, 66% over two steps; (i) TBAF, THF, rt, 89%; (j) NaOH, THF/MeOH/H2O, rt, 94%.
OH
OH
Boc
N
Boc
N
a
Table 1
NR'R''
SAR of benzamides synthesized via Scheme 3
CO2H
22
23a-j
Compds Human EC50 (nM)a (%Act)b
Human IC50 (nM)
b1 b2
hERGc IC50
(lM)
O
OH
b3
H
N
b
24a
24b
24c
24d
24e
24f
24g
24h
24i
24 (84%)
63 (95%)
3.3 (89%)
1.9 (85%)
9.7 (100%)
0.49 (90%)
75 (97%)
1.7 (101%)
3.1 (97%)
5.4 (97%)
>20,000 5200
>20,000 10900
>20,000 5600
>20,000 11000
>20,000 >20,000 >60
>20,000 13400 7.0
>20,000 >20,000 12
>20,000 >20,000 55
>20,000 >20,000 36
>20,000 >20,000 17
>30
8.3
46
NR'R''
NH2
24a-j
O
S
31
H
H
CO2Et
CO2Et
H
N
24a
H
N
N
24f
N
CO2Et
O
24b
24c
N
H
24g
24h
24j
O
a
H
Values reported are the minimum of four experiments except 24a (two) and
24b (three).
O
b
H
N
N
N
%
activation defined as the fitted maximal value of the test compound
N
concentration response expressed as
a percent of the maximal response to
O
H
H
O
R-(À)-isoproterenol.
O
Me
Me
c
Me
IKr binding assay, Ref. 19. Binding at the hERG and other ion channels were
measured to examine possible cardiac liabilities of these compounds.
H
H
N
N
N
N
24i
24d
24e
N
N
N
Me
SO2Et
N
N
N
24h
Scheme 3. Synthesis of the benzamides. Reagents and conditions: (a) amine, EDC,
HOAt or HOBt, Pr2NEt, DMF; (b) TFA, CH2Cl2 or HCl, dioxane/CH2Cl2.
H
H
H
i
b, c
d, e
h, i
O
a
CO2Et
CONHNH2
H
H
N
N
H
H
N
N
HN
HN
N
Boc
Boc
27h
25
26
H
appeared to greatly improved potency (EC50 = 3.3 nM). Substitu-
tions on the lactone ring were tolerated (24d, EC50 = 1.9 nM). Sul-
fone replacement 24e also improved b3 potency (EC50 = 9.7 nM)
compared with ester 24b (EC50 = 63 nM). Another significant
potency improvement was achieved via piperidine cyclization to
a 3.1.0 azabicyclic system such as 24f. Exo substituted bicylic com-
pound 24f possessed sub-nanomolar potency (EC50 = 0.49 nM)
while its endo isomer 24g was much less active (EC50 = 75 nM).
Follow-up work on the exo bicyclic ester 24f series included
many heteroaromatic rings designed as ester bioisosteres.20 The
synthesis of selected heteroaryls is illustrated in Scheme 4. Boc
protected exo azabicyclic ester 25 was converted to hydrazide 26
which was heated with triethyl orthoformate to form the oxadia-
zole ring. Then Boc deprotection gave oxadiazole 27h. Ethyl
oxadiazole 27i was made in a similar fashion, using triethyl
orthopropionate instead of orthoformate. Methyl tetrazole 27j
was synthesized from carboxylic acid 28. Thus primary amide for-
mation via mixed anhydride intermediate gave 29 which was then
O
Me
N
27i
H
H
H
N
f, g
NH
CO2H
H
CONH2
H
H
N
N
N
N
N
Boc
Boc
Boc
28
29
30
j, k
H
N
Me
N
H
N
N
HN
27j
Scheme 4. Synthesis of the heteroaryls. Reagents and conditions: (a) NH2NH2ÁH2O,
THF/MeOH, rt, 75%; (b) CH(OEt)3, 110 °C, 65%; (c) TFA, CH2Cl2; (d) CEt(OEt)3, 110 °C;
(e) HCl, dioxane; 71% over two steps; (f) EtOCOCl, Et3N, THF, À20 °C to À10 °C, (g)
NH3, MeOH, rt, 66% over two steps; (h) (CF3CO)2O, Et3N, THF, À20 °C to 0 °C, 71%;
(i) NaN3, NH4Cl, DMF, 110 °C, 91%; (j) K2CO3, MeI, DMF, rt, 50%; (k) HCl,
dioxane/MeOH; 99%.

58
C. Zhu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 55–59
Table 2
Pharmacokinetic profiles of selected b3 adrenergic agonistsa
Compds
Species
Clp (mL/min/kg)
Vd (L/kg)
t1/2 (h)
PO AUCnorm
(l
MÁh/mpk)
F (%)
24c
Rat
Dog
56
31
7.2
7.4
2.5
3.2
0.21
0.23
31
17
24d
24h
24i
Rat
Rat
86
62
9.5
9.0
2.0
1.4
0.16
0.26
38
43
Rat
Dog
Rhesus
56
36
30
9.3
9.2
5.2
3.0
3.7
2.4
0.21
0.46
0.06
33
44
5
24j
Rat
Dog
29
19
6.5
5.5
3.2
3.7
0.73
0.99
56
51
a
Rat iv: 1 mpk, po: 2 mpk; dog iv: 0.5 mpk, po: 2 mpk.
converted to CN. Tetrazole formation, methylation followed by Boc
deprotection afforded tetrazole 27j. Heteroaryl amines 27h, 27i,
27j were then coupled with acid 22 (Scheme 3) to afford 24h,
24i, 24j respectively. We were pleased to find that heteroaromatic
rings as ester bioisosteres were well tolerated. As shown in
Table 1, 24h (EC50 = 1.7 nM), 24i (EC50 = 3.1 nM) and 24j
(EC50 = 5.4 nM) were all very active at the human b3-AR. Notably,
they also had excellent selectivity over the b1 and b2-ARs.
amides. However, due to overall suboptimal half-lives in
preclinical species, further optimization was needed in the benza-
mide series to achieve a QD dosing prediction in humans. Those
results as well as in vivo pharmacodynamic effects will be reported
in due course.
Acknowledgment
Pharmacokinetic profiles of selected b3 adrenergic agonists are
shown in Table 2. Lactone 24c had a moderate to high plasma
clearance relative to hepatic blood flow, a short half-life and low
to moderate oral bioavailability in rats and dogs. In incubations
with liver microsomes, the order of stability was dog > human,
rat (% parent @ 45 min = 78% dog, 53% human, 56% rat), which indi-
cated that the half-life in humans may also be short. Since the lac-
tone ring-opened acid alcohol was the major metabolite identified
in hepatocyte incubation studies, several substituted lactones such
as dimethyl substituted 24d were synthesized to increase the lac-
tone stability toward hydrolysis. However, despite the fact that no
lactone ring-opened metabolite was detected in hepatocyte incu-
bations with 24d, there was no improvement in rat PK. We then
turned our attention to ester bioisosteres. Oxadiazole 24h again
showed high in vivo plasma clearance and short half-life in rats.
Ethyl oxadiazole 24i had an improved rat half-life compared with
24h, however its half-life in dogs was still short (t1/2 = 3.7 h) and
the overall rhesus PK profile was suboptimal with respect to oral
bioavailability and half-life. Methyl tetrazole 24j afforded a better
clearance (29 mL/min/kg), half-life (t1/2 = 3.2 h) and bioavailability
(56%) in rats, unfortunately its dog half-life was still suboptimal
(t1/2 = 3.7 h). The preclinical DMPK profiles indicated that
compounds in Table 2 had high risk for short t1/2 and low
probability of success for QD dosing in humans. Oxadiazole 24h
showed good overall stability in microsomal incubations
(% parent @ 45 min = rat, 98% > human, 84% ꢀ rhesus, 80% > dog,
73%) and hepatocyte incubations (P85% parent @ 60 min in
human/rat/dog hepatocytes). Thus for oxadiazole 24h, it’s likely
that other pathways such as elimination of intact drug are involved
in its elimination.
The authors would like to thank Alka Bansal, Donna Hreniuk
and Scott Feigner for in vitro assay support.
Supplementary data
Supplementary data (general procedures are provided for b3
cAMP assay and b1 and b2 binding assay) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/10.
1016/j.bmcl.2015.11.030.
References and notes
1. Arch, J. R. S.; Ainsworth, A. T.; Cawthorne, M. A.; Wilson, C.; Wilson, S. Nature
1984, 309, 163.
2. Strosberg, A. D. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 421.
3. (a) Weber, A. E. Annu. Rep. Med. Chem. 1998, 33, 193; (b) Hu, B.; Jennings, L. L.
Prog. Med. Chem. 2003, 41, 167; (c) Sawa, M.; Harada, H. Curr. Med. Chem. 2006,
13, 25.
4. (a) Fujimura, T.; Tamura, K.; Tsutsumi, T.; Yamamoto, T.; Nakamura, K.;
Koibuchi, Y.; Kobayashi, M.; Yamaguchi, O. J. Urol. 1999, 161, 680; (b) Igawa, Y.;
Yamazaki, Y.; Takeda, H.; Hayakawa, K.; Akahane, M.; Ajisawa, Y.; Yoneyama,
T.; Nishizawa, O. Br. J. Pharmacol. 1999, 126, 819.
5. Yamaguchi, O.; Chapple, C. R. Neurourol. Urodyn. 2007, 26, 752.
6. Takeda, M.; Obara, K.; Mizusawa, T.; Tomita, Y.; Arai, K.; Tsutsui, T.; Hatano, A.;
Takahashi, K.; Nomura, S. J. Pharmacol. Exp. Ther. 1999, 288, 1367.
7. (a) Woods, M.; Carson, N.; Norton, N. W.; Sheldon, J. H.; Argentieri, T. M. J. Urol.
2001, 166, 1142; (b) Kaidoh, K.; Igawa, Y.; Takeda, H.; Yamazaki, Y.; Akahane,
S.; Miyata, H.; Ajisawa, Y.; Nishizawa, O.; Andersson, K. E. J. Urol. 2002, 168,
1247; (c) Takeda, H.; Yamazaki, Y.; Igawa, Y.; Kaidoh, K.; Akahane, S.; Miyata,
H.; Nishizawa, O.; Akahane, M.; Andersson, K. E. Neurourol. Urodyn. 2002, 21,
558.
8. (a) Tyagi, P.; Tyagi, V.; Yoshimura, N.; Chancellor, M.; Yamaguchi, O. Drugs
Future 2009, 34, 635; (b) Hieble, P. J. Curr. Top. Med. Chem. 2007, 7, 207; (c)
Igawa, Y.; Michel, M. C. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2013, 386, 177;
(d) Andersson, K.; Martin, N.; Nitti, V. J. Urol. 2013, 190, 1173.
9. (a) Wada, Y.; Shirahashi, H.; Iwanami, T.; Ogawa, M.; Nakano, S.; Morimoto, A.;
Kasahara, K.-I.; Tanaka, E.; Takada, Y.; Ohashi, S.; Mori, M.; Shuto, S. J. Med.
Chem. 2015, 58, 6048; (b) Abe, Y.; Ota, E.; Endo, T.; Murakami, M.; Kobayashi,
M. Pharmazie 2014, 69, 881; (c) Hattori, K.; Toda, S.; Imanishi, M.; Itou, S.;
Nakajima, Y.; Washizuka, K.; Araki, T.; Hamashima, H.; Tomishima, Y.; Sakurai,
M.; Matsui, S.; Imamura, E.; Ueshima, K.; Yamamoto, T.; Yamamoto, N.;
Ishikawa, H.; Nakano, K.; Unami, N.; Hamada, K.; Matsumura, Y.; Takamura, F. J.
Med. Chem. 2009, 52, 3063.
10. Takasu, T.; Ukai, M.; Sato, S.; Matsui, T.; Nagase, I.; Maruyama, T.; Sasamata,
M.; Miyata, K.; Uchida, H.; Yamaguchi, O. J. Pharmacol. Exp. Ther. 2007, 321, 642.
11. Sacco, E.; Bientinesi, R.; Tienforti, D.; Racioppi, M.; Gulino, G.; D’Agostino, D.;
Vittori, M.; Bassi, P. Expert Opin. Drug Discov. 2014, 9, 433.
12. (a) Morriello, G. J.; Wendt, H. R.; Bansel, A.; Di Salvo, J.; Feighner, S.; He, J.;
Hurley, A. L.; Hreniuk, D. L.; Salituro, G. M.; Reddy, M. V.; Galloway, S. M.;
McGettigan, K. K.; Laws, G.; McKnight, C.; Doss, G. A.; Tsou, N. N.; Black, R. M.;
In summary, after development of a novel stereoselective syn-
thesis of pyrrolidine acid intermediate 22, optimization of the
right-hand side of the molecule led to the discovery of a novel
pyrrolidine benzamide (reverse amide) lead as a potent and selec-
tive human b3-adrenergic receptor agonist.21 Follow-up designs
from initial hit piperidine 24b, discovered from library synthesis,
included lactone 24c and azabicyclic ester 24f which both
exhibited greatly improved human b3-AR potency. Heteroaryls
(24h, 24i, 24j) were designed as ester bioisosteres, and they were
well tolerated with respect to b3-AR potency. Many reverse amides
achieved the same b3 potency as some previously reported aniline

C. Zhu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 55–59
59
Morris, J.; Ball, R. G.; Sanfiz, A. T.; Streckfuss, E.; Struthers, M.; Edmondson, S. D.
Bioorg. Med. Chem. Lett. 1865, 2011, 21; (b) Moyes, C. R.; Berger, R.; Goble, S. D.;
Harper, B.; Shen, D.-M.; Wang, L.; Bansal, A.; Brown, P. N.; Chen, A. S.; Dingley,
K. H.; Di Salvo, J.; Fitzmaurice, A.; Gichuru, L. N.; Hurley, A. L.; Jochnowitz, N.;
Miller, R. R.; Mistry, S.; Nagabukuro, H.; Salituro, G. M.; Sanfiz, A.; Stevenson, A.
S.; Villa, K.; Zamlynny, B.; Struthers, M.; Weber, A. E.; Edmondson, S. D. J. Med.
Chem. 2014, 57, 1437.
1960, 1988, 31; (b) Kagechika, H.; Kawachi, E.; Hashimoto, Y.; Himi, T.; Shudo,
K. J. Med. Chem. 1988, 31, 2182.
17. Giordano, C.; Cavicchioli, S.; Levi, S.; Villa, M. J. Org. Chem. 1991, 56, 6114.
18. For a more efficient synthesis later developed: Xu, F.; Chung, J. Y. L.; Moore, J.
C.; Liu, Z.; Yoshikawa, N.; Hoerrner, R. S.; Lee, J.; Royzen, M.; Cleator, E.; Gibson,
A. G.; Dunn, R.; Maloney, K. M.; Alam, M.; Goodyear, A.; Lynch, J.; Yasuda, N.;
Devine, P. N. Org. Lett. 2013, 15, 1342.
13. Edmondson, S. D.; Zhu, C.; Kar, N. F.; Di Salvo, J.; Nagabukuro, H.; Sacre-Salem,
B.; Dingley, K.; Berger, R.; Goble, S. D.; Morriello, G.; Harper, B.; Moyes, C. R.;
Shen D.-M.; Wang, L.; Brown, P. N.; Chen, A. S.; Fitzmaurice, A.; Frenkl, T.;
Gichuru, L. N.; Hurley, A. L.; Jochnowitz, N.; Mistry, S.; Miller, R. R.; Ormes, J.;
Salituro, G. M.; Sanfiz, A.; Stevenson, A. S.; Villa, K.; Zamlynny, B.; Green, S.;
Struthers, M; Weber, A. E. J. Med. Chem., submitted.
14. Mathvink, R. J.; Tolman, J. S.; Chitty, D.; Candelore, M. R.; Cascieri, M. A.;
Colwell, L. F., Jr.; Deng, L.; Feeny, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D.
E.; Miller, R. R.; Stearns, R. A.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E.
J. Med. Chem. 2000, 43, 3832.
19. Lynch, J. J.; Wallace, A. A.; Stupienski, R. F.; Baskin, E. P.; Beare, C. M.; Appleby,
S. D.; Salata, J. J.; Jurkiewicz, N. K.; Sanguinetti, M. C.; Stein, R. B. J. Pharmacol.
Exp. Ther. 1994, 269, 541.
20. For an excellent review of bioisosteres in drug design, see (a) Meanwell, N. A. J.
Med. Chem. 2011, 54, 2529; For specific examples of ester bioisostere, see (b)
Street, L. J.; Baker, R.; Book, T.; Kneen, C. O.; MacLeod, A. M.; Merchant, K. J.;
Showell, G. A.; Saunders, J.; Herbert, R. H.; Freedman, S. B.; Harley, E. A. J. Med.
Chem. 1990, 33, 2690; (c) Saunders, J.; Cassidy, M.; Freedman, S. B.; Harley, E.
A.; Iversen, L. L.; Kneen, C.; MacLeod, A. M.; Merchant, K.; Snow, R. J.; Baker, R. J.
Med. Chem. 1990, 33, 1128.
15. Kalgutkar, A. S. Curr. Med. Chem. 2015, 22, 438.
21. Edmondson, S. D.; Berger, R.; Chang, L.; Colandrea, V. J.; Hale, J. J.; Harper, B.;
Kar, N. F.; Li, B.; Moriello, G. J.; Moyer, C. R; Sha, D.; Shen, D.-M.; Wang, L.;
Wendt, H. R.; Zhu, C., PTC Int. Appl. WO 2011025690, 2011.
16. For examples of reverse amide in drug discovery, see (a) Summers, J. B.; Gunn,
B. P.; Martin, J. G.; Martin, M. B.; Mazdiyasni, H.; Stewart, A. O.; Young, P. R.;
Bouska, J. B.; Goetz, A. M.; Dyer, R. J.; Brooks, D. W.; Carter, G. W. J. Med. Chem.