BMS-201620: A selective beta 3 agonist

Article abstract of DOI:10.1016/j.bmcl.2004.04.074

A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human β₃ adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent β₃ full agonist (K_i=93nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.

Full text of DOI:10.1016/j.bmcl.2004.04.074

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3525–3529
BMS-201620: a selective beta 3 agonist
W. N. Washburn,* C.-Q. Sun,* G. Bisacchi, G. Wu, P. T. Cheng, P. M. Sher, D. Ryono,
A. V. Gavai, K. Poss, R. N. Girotra, P. J. McCann, A. B. Mikkilineni, T. C. Dejneka,
T. C. Wang, Z. Merchant, M. Morella, C. M. Arbeeny, T. W. Harper, D. A. Slusarchyk,
S. Skwish, A. D. Russell, G. T. Allen, B. Tesfamariam, B. H. Frohlich, B. E. Abboa-Offei,
M. Cap, T. L. Waldron, R. J. George, D. Young, K. E. Dickinson and A. A. Seymour
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543, USA
Received 3 February 2004; accepted 19 April 2004
Available online
Abstract—A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human b3
adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent b3 full agonist (Ki ¼ 93 nM,
93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.
Ó 2004 Elsevier Ltd. All rights reserved.
The alarming increase in the incidence of obesity and
noninsulin dependent diabetes mellitus is of great con-
cern to health authorities of Western countries.1 An
attractive approach to treating these conditions entails
increasing metabolic energy expenditure by selective
activation of the b3 adrenergic receptor.2 As previously
described,3;4 our strategy has been to utilize full rather
than partial b3 agonists to enhance the probability of
eliciting a thermogenic response from any brown adi-
pose tissue (BAT) that may be present in man. Conse-
quently, the high b3 agonist intrinsic activity (IA) of
4-hydroxy-3-methylsulfonanilidoethanolamines ensured
our continuing interest despite a poor prognosis for
bioavailability.
focuses on the enhanced b3 selectivity generated by a
conformationally rigid carboxamide spacer joining the
second aryl ring to Ca.
The promising selectivity obtained with compound 3
with R,S stereochemistry prompted further investiga-
tion. To establish the stereochemical preference, the R,R
isomer 4 was also prepared. The 80-fold greater b3
affinity and 15- to 40-fold greater selectivity for b3 versus
b1 and b2 of isomer 3 compared to isomer 4 established
the preferred glycinamide stereochemical orientation to
be S. This preference for the configuration of Ca to be S
for the arylglycine series 3 and R for 2 reflects an iden-
tical spatial projection of the p-anisyl moiety into a
common pocket of the b3 receptor. The 162-fold binding
selectivity of 3 versus b2 was particularly striking, espe-
cially since the two series represented by compounds 1
and 2 rarely exhibited more than 13-fold b2 selectivity.3;4
Prior explorations of this chemotype had revealed that
incorporation of benzyl amines containing a para
hydrogen bonding acceptor (e.g., p-OMe, Table 1)
enhanced b3 affinity and selectivity, especially if a second
aryl ring was attached to Ca via a 0 or 1 atom linker to
reduce the conformational flexibility. We have presented
SAR wherein the linker is a single bond (1,1-diaryl-
methylamines) or a methylene (1,2-diaryl-ethylamines)
exemplified by 1 and 2, respectively.3;4 This paper
The initial SAR revealed tertiary anilides were not tole-
rated since N-methylation of 3 to generate 5 resulted in a
90-fold loss of b3 affinity. Elongation of this spacer also
proved unfavorable since homologation of 3 to generate
benzyl amide 6 decreased b3 affinity and b2 selectivity
8- and 3-fold, respectively. It is essential that the
planarity of the aniline ring be maintained. Upon
replacement of the anilide moiety of 3 with a t-Bu amide
(9) or a cyclohexyl amide (10), selectivity was main-
tained; but, b3 affinity decreased 25- and 19-fold,
* Corresponding authors. Fax: +1-609-818-3550; e-mail addresses:
william.washburn@bms.com; chongqing.sun@bms.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.074

3526
W. N. Washburn et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3525–3529
Table 1. Comparison of b adrenergic profiles of compounds 1–115
Cα
OH
H
N
CH3SO2NH
HO
R
OMe
Compound
R
b3 Ki (nM)
b3 IA (% act)
Selectivityb versus
b1
b2
1a
2
Ph-4-OMe
(R)-CH2Ph
81
44
100
99
90
45
78
105
92
29
80
95
99
17
22
8
60
60
4
3
(S)-CONHPh
(R)-CONHPh
(S)-CON(Me)Ph
(S)-CONHCH2Ph
(S)-CONH2
370
162
4
4
30,000
33,000
3100
5
4
3
6
39
46
4
55
31
7
2910
8
(R)-CONH2
14,100
9600
7000
3.5
9
(S)-CONH-t-Bu
(S)-CONH-c-hexyl
(S)-CO-piperidine
>100
>14
15
>100
>100
10
10
11
10,000
a Racemate.
b Selectivity is defined as the ratio of b1 Ki or b2 Ki to b3 Ki.
respectively. The weak affinity and diminished selectivity
of the piperidinyl amide 11 is consistent with the need
for planar secondary amides. The contribution of each
aryl ring to b3 selectivity and affinity of 3 was ascer-
tained. Upon deletion of the a-anisyl ring (12), b3
affinity diminished 22-fold (b3 Ki ¼ 8200 nM) relative to
that of 3; selectivity versus b1 and b2 was abolished. In
contrast, b3 affinity of 7, the primary amide counterpart
of 3, was reduced 8-fold relative to that of 3, with no
change in b1 and 5-fold diminution in b2 selectivity.
more; consequently, selectivity versus b1 and b2 dimin-
ished as much as 5-fold. With respect to a-aryl ring
O
NH
O
HN
O
CH3
CH3
b - d
a
MeO
MeO
H
N
H2N
CO2Et
CH3
CO2H
CH3
Ac
e, f
Compounds 3–11 were prepared from the appropriate
arylglycine.8 Following sequential Cbz protection, EDC
or EEDQ mediated amide formation, and hydrogeno-
lysis over Pd(OH)2, the resulting arylglycinamide was
condensed at 110 °C in THF/EtN(i-Pr)2 with iodide 13.9
Sequential deprotection mediated by NH4F and then
H2/Pd/MeOH yielded 3–11. During the condensation
with 13, partial epimerization of the arylglycinamide
typically occurred thereby necessitating preparative
HPLC purification of the final product.10
(L)-α-MeBnNH2
MeO
MeO
TBS
TBS
O
O
O
H
CH3SO2NH
BnO
N
CH3SO2NH
BnO
I
OEt
CH3
13
g
MeO
O
TBS
O
H
N
CH3SO2NH
HO
OH
h, i
OH
OH
H
N
H
N
CH3
CH3SO2NH
HO
CH3SO2NH
NH HO
Me
MeO
O
PO3Et2
H3CO
12
PO3Et2
22
OH
O
H
N
CH3SO2NH
HO
N
H
NH2
j, k
CH3
Prior to embarking on an extensive SAR study, the
consequence of quarternization of the a-carbon of 3
to preclude epimerization was ascertained, and the
p-hydrogen bonding acceptor of the a-aryl ring opti-
mized. All of the a-methylated arylglycinamides were
prepared as shown in Scheme 1.10 Comparison of 3, 14,
and 15 to their respective a-methylated counterparts 16,
17, and 18 (Table 2) revealed methylation increased b3
affinity ꢀ5- to 10-fold and maintained full b3 agonist
activity. However, b1 and b2 affinity was enhanced even
39
MeO
Scheme 1. Reagents and conditions: (a) (NH4)2CO3, NaCN, DMF,
76%; (b) NaOH/H2O, 95%; (c) Ac2O, 100%; (d) ( )-a-methylbenzyl-
L
amine, EtOH, 50%; (e) concd HCl/H2O; (f) EtOH, HCl, 84% (two
steps); (g) diisopropylethylamine, diglyme, 145 °C, 65%; (h) LiOH/
MeOH/THF/H2O; (i) H2, Pd/C, MeOH, 90% (two steps); (j) EDC,
HOAt, 5:1 DCE/DMF, 20 °C; (k) NH4F, MeOH/HOAc, 64% (two
steps).

W. N. Washburn et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3525–3529
3527
Table 2. Comparison of b3 AR agonist activity and selectivity versus b1 and b2 as a consequence of a-methylation5
OH
O
H
N
X
CH3SO2NH
N
H
R
HO
H3CO
Compound
R
X
H
b3 Ki (nM)
b3 IA (% act)
Selectivitya versus
b1
b2
3
H
370
280
89
90
85
60
15
32
11
9
162
89
14
15
16
17
18
H
3,4-OCH2O–
4-Cl
H
101
119
97
573
81
Me
Me
Me
H
77
33
3,4-OCH2O–
4-Cl
38
100
8.8
117
15
a Selectivity is defined as the ratio of b1 Ki or b2 Ki to b3 Ki.
substitution, 16 was found to be superior to 19, 20, and
21 (Table 3), presumably reflecting the superior hydro-
gen bonding capability and better accommodation of
the steric demands of the para methoxyl substituent.
demands increased. In contrast, any nonpolar para
substituent, even OPh (33), bound to b3 with ꢀ5-fold
higher affinity than the unsubstituted parent 16. meta–
para Annelation to generate bicyclic entities (17) and
(37) was favorable. The b3 binding pocket also accom-
modated para polar groups such as OH (36), CONHPr
(38), or CH2PO(OEt)2 (39); whereas, b3 affinity was
diminished 5-fold for meta polar moieties such as OH
(35). meta or para Substitution with either cationic (40,
41, 42) or anionic (43, 44, 45) substituents was unfa-
vorable, particularly if the charge was in close proximity
to the anilide ring as in the case of 43.
The importance of the conformation restriction imposed
by the carboxamide moiety is readily apparent upon
comparison of 16 with 22 for which the carboxamide
linkage was replaced with a flexible ethano tether. Al-
though 22 exhibited similar b3 affinity (59 nM) to that of
16, the 1000-fold increase in b1 (0.8 nM) and b2 (1.1 nM)
affinity abolished both b1 and b2 selectivity.
The salient b3 agonist SAR for analogs of 16 arising
from modification of the anilide moiety is illustrated in
Table 4. The effect of substituent position is readily
apparent from the regioisomeric dependence of b3 Ki
upon methylation, methoxylation, and chlorination of
16 to generate sets 23–25, 29–31, and 18, 26–27,
respectively. para Substitution was more favorable than
meta, which in turn was strongly preferred to ortho. In
every instance, ortho substitution was deleterious; even
ortho fluorination of 18 to form 28 decreased b3 affinity
3-fold. Affinity relative to hydrogen was increased by
lipophilic meta substituents such as Me (24) or Cl (27) or
Br (34) whereas the unfavorable interactions of a more
hydrophilic meta phenolic ethers such as methoxy (30)
or PhO (32) progressively diminished affinity as steric
The impact of anilide substitution on selectivity is more
complex. In general, b1 and b2 affinities were not altered
by ortho or meta substitution. Consequently, selectivity,
being solely dependent on b3 affinity, varied accordingly.
Only modest selectivity perturbations were observed
upon para substitution since affinity to all three recep-
tors tended to be commensurately enhanced. Our crite-
ria for in vivo evaluation were high b3 binding selectivity
and reduced potency and/or partial agonist activity in a
b1 functional assay measured using spontaneously
beating guinea pig atria.11 Diminished b1 IA of <20%
were determined for lipophilic agonists, such as dichlo-
rides 46 and 47 or trichloride 48, suggesting that there
was an apparent inverse correlation of b1 IA with ACD
log P values (r2 ¼ 0:62, P < 0:0001, n ¼ 28). The b1
Table 3. Comparison of b3 AR agonist activity and selectivity versus b1 and b2 as a consequence of substitution of the a-aryl ring5
OH
O
H
N
CH3SO2NH
N
H
CH3
HO
Z
Compound
Z
b3 Ki (nM)
b3 IA (% act)
Selectivitya versus
b1
b2
81
16
19
20
21
OMe
Br
77
950
400
190
119
69
11
6
13
150
75
CONH2
OCHF2
77
105
40
17
a Selectivity is defined as the ratio of b1 Ki or b2 Ki to b3 Ki.

3528
W. N. Washburn et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3525–3529
5
Table 4. SAR for anilide substitution for b3 AR agonist activity and selectivity versus b1 and b2
OH
O
H
N
X
CH3SO2NH
HO
N
H
CH3
H3CO
Compound
X
b3 Ki (nM)
Selectivitya versus
EC50 b1 (% IA)b
ACD log P
b1
b2
80
16
17
23
24
25
26
27
18
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
H
77
33
11
9
1200 (95)
950 (93)
2.36
2.56
2.82
2.82
2.82
2.55
3.08
3.32
3.38
2.25
2.53
2.37
4.49
3.93
2.85
2.00
1.61
2.55
2.49
2.2
3,4-OCH2O–
2-CH3
3-CH3
38
3
2200
61
1
4500 (83)
5300 (73)
1100 (90)
17
19
4
74
39
12
59
67
79
4
4-CH3
2-Cl
28
380
17
3-Cl
4-Cl
27
9
1700 (50)
4300 (62)
56,000 (43)
15,000 (60)
500 (85)
15
47
2-F-4-Cl
2-OCH3
3-OCH3
32
2
3100
142
17
14
8
46
65
23
17
116
32
139
173
11
194
209
23
1
4-OCH3
3-OPh
140 (85)
490
14
5
4-OPh
3-Br
3
19
54
6
13,700 (50)
750 (96)
300 (90)
3-OH
4-OH
340
23
11
66
7
3,4-NC(Me)S–
4-CONHPr
4-CH2PO3Et2
3-CH2NH2
3-O(CH2)2NMe2
4-O(CH2)2NMe2
3-CO2H
3-OCH2CO2H
4-OCH2CO2H
3,4-Cl2
11
20
1700 (70)
93
51
63
10
3
2400 (55)
12,000 (91)
23,600 (85)
1600 (92)
115
520
260
1800
450
370
24
1.23
2.38
2.23
ꢁ0.67
1.73
1.58
3.92
3.82
4.53
2.44
2.40
10
30
4
38
138
65
32
16
13
313
281
4600 (87)
3200 (100)
48,000 (8)
16,000 (13)
34,000 (15)
2100 (89)
36
21
51
35
79
3,5-Cl2
71
51
3,4,5-Cl3
3,4-(OCH3)2
3,4,5-(OCH3)3
46
370
23,000 (66)
a Selectivity is defined as the ratio of b1 Ki or b2 Ki to b3 Ki.
bb1 IA determined using spontaneously beating guinea pig atria by measuring contraction acceleration relative to isoproterenol response.11
blocker activity exhibited by 46 during in vivo charac-
terization summarized in Table 5 was in accord with this
finding.
Table 5. In vivo response in African green monkeys (iv)
OH
O
H
N
Upon ivadministration to ketamine anesthetized Afri-
can green monkeys (AGM), the in vitro/in vivo corre-
lation in this series was particularly poor since most of
the compounds were devoid of in vivo activity (Table 5).
Serum stability was acceptable; whereas, both intestinal
and hepatic first pass glucuronidation were rapid. A
dose response was determined for those compounds
which produced a statistically significant elevation in
free fatty acid (FFA) unaccompanied by b2 mediated
decrease in serum Kþ concentrations12 or b1 or b2
induced tachycardia (HR). Efforts to exploit the dimi-
nution of b1 IA to minimize onset of tachycardia were
frustrated by weak in vivo b3 activity of lipophilic
agonists such as 46.
X
CH3SO2NH
HO
N
H
CH3
H3CO
Compd
R
b3 Ki
(nM)
AGM response to 0.1
mg/kg ivdose
DHR
DKþ
DFFA
27
34
18
38
39
46
17
37
3-Cl
3-Br
4-Cl
17
19
15
20
þ2
ꢁ0.14
þ0.1
þ0.9ꢂ
þ0.37
þ0.88ꢂ
þ0.7
þ11
þ2
þ0.5
4-CONHPr
þ23
þ11
ꢁ11
þ16
þ3
þ0.1
4-CH2PO(OEt)2 93
ꢁ0.24
þ0.19
þ0.33
þ0.06
þ0.7ꢂ
þ0.39
þ0.73ꢂ
þ0.4
3,4-Cl2
3,4-OCH2O–
3,4-NC(Me)S–
24
33
11
Table 6 summarizes the in vivo potency and the func-
tional margin of separation between b3 mediated effects
* p < 0:05.

W. N. Washburn et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3525–3529
3529
Table 6. Dose response of African green monkeys (ivadministration)
Compd Lipolysis
b1 Margina before b2 Margina before
ED50 (mg/kg) onset of tachycardia decrease serum Kþ
Amos, A. F.; McCarty, D. J.; Zimmet, P. Diabet. Med.
1997, 14, S7.
2. For recent reviews, see: (a) Lowell, B. B.; Bachman, E. S.
J. Biol. Chem. 2003, 278, 29385; (b) de Souza, C. J.;
Burkey, B. F. Curr. Pharm. Des. 2001, 7, 1433; (c) Weyer,
C.; de Souza, C. J. Drug Dev. Res. 2000, 51, 80; (d) Bray,
G. A.; Tartaglia, L. A. Nature 2000, 404, 672; (e) Weyer,
C.; Gautier, J. F.; Danforth, E., Jr. Diabet. Metab. 1999,
25, 11; (f) Kordik, C. P.; Reitz, A. B. J. Med. Chem. 1999,
42, 181; (g) Weber, A. E. Annu. Rep. Med. Chem. 1998, 33,
193.
3. Washburn, W. N.; Sher, P. M.; Poss, K.; Girotra, R. N.;
McCann, P. J.; Gavai, A. V.; Mikkilineni, A. B.; Mathur,
A.; Cheng, P.; Dejneka, T. C.; Sun, C. Q.; Wang, T. C.;
Harper, T. W.; Russell, A. D.; Slusarchyk, D. A.; Skwish,
S.; Allen, G. T.; Hillyer, D. E.; Frohlich, B. H.; Abboa-
Offei, B. E.; Cap, M.; Waldron, T. L.; George, R. J.;
Tesfamariam, B.; Ciosek, C. P.; Young, D. A.; Dickinson,
K. E.; Seymour, A. A.; Arbeeny, C. M.; Gregg, R. E.
Bioorg. Med. Chem. Lett. 2001, 11, 3035.
4. Gavai, A. V.; Sher, P. M.; Mikkilineni, A. B.; Poss, K. M.;
McCann, P. J.; Girotra, R. N.; Fisher, L. G.; Wu, G.;
Bednarz, M. S.; Mathur, A.; Wang, T. C.; Sun, C. Q.;
Slusarchyk, D. A.; Young, D. A.; Dickinson, K. E.;
Seymour, A. A.; Arbeeny, C. M.; Washburn, W. N.
Bioorg. Med. Chem. Lett. 2001, 11, 3041.
5. Receptor binding assays were run in triplicate with
membranes prepared from CHO cells expressing the three
cloned human b receptors in the presence of 125I-iodo-
cyanopindolol;6 b3 AR agonist activity was assessed by
measurement of cAMP accumulation levels in CHO
membranes expressing human b3 AR.7 IA is the percent
of the maximal stimulation achieved with isoproterenol.
6. All compounds were evaluated using the truncated human
b3 adrenergic receptor reported by Emorine, L. T.;
Marullo, S.; Briend-Sutren, M. M.; Patey, G.; Tate, K.;
Delavier-Klutchko, C.; Strosberg, A. D. Science 1989, 245,
1118.
17
18
39
0.08
0.07
0.1
>1<6
>7
>25
>6
>7
>25
>25
>60
196085 0.03
194449 0.08
>3<5
>6<12
aThe margin of separation was the ratio of the dose that produced the
onset (statistically significant) of a b1 or b2 event to the ED50 for
lipolysis.
and b1 or b2 dependent events in ketamine anesthetized
African green monkeys. Compound 39 was unique
among all the arylglycinamides with respect to the safety
margin magnitude. This margin was superior to that of
the other two BMS b3 agonists, 1,1-diarylmethylamine
BMS-1944493 and 1,2-diarylethyl-amine BMS-196085,4
that entered clinical trials.
The unfavorable biophysical and PK profile of 39 did
not differ from that of other arylglycinamides. Rat and
AGM oral bioavailability of less than 1–2% were con-
sistent with Caco-2 permeability of 6–20 nm/sec. Fol-
lowing ivadministration a low Vss of ꢀ2.5 L/kg and high
clearance of 68 mL/min/kg combined to produce a t1=2 of
1 h in AGM. Despite these inauspicious values, we
continued to pursue 39 in hopes that the large safety
margin, full b3 IA and good b3 affinity would produce a
definitive indication whether b3 agonists could elicit a
sustained robust thermogenic response in man.
Intravenous administration of 39 to six volunteers pro-
duced no separation between the onset of lipolysis and
prolongation of QT interval.13 Further studies with 39
(BMS-201620) were terminated.
7. Sher, P. M.; Fisher, L. G.; Skwish, S.; Michel, I. M.;
Seiler, S. M.; Washburn, W. N.; Dickinson, K. E. J. Med.
Chem. Res. 1997, 7, 109.
8. For the synthesis of the enantiomers of i, see Crast L. B.
U.S. Patent 3,517,023, 1970; Chem. Abstr. 1970, 466567.
O
Acknowledgements
H2N
OH
We acknowledge the contributions of members of the
Bristol-Myers Squibb analytical chemistry department;
A. D. Strosberg for providing transfected CHO cells.
MeO
i
9. Preparation of 13 analogous to 25 of Ref. 3.
10. Spectral data were fully consistent with structures.
11. Tesfamariam, B.; Allen, G. T. Br. J. Pharmacol. 1994, 112,
55.
References and notes
12. Lipworth, B. J.; McFarlane, L. C.; Coutie, W. J.;
McDevitt, D. Eur. J. Clin. Pharmacol. 1989, 37, 297.
13. Unpublished work communicated by Dr. Peter Slugg.
1. (a) Yanovski, S. Z.; Yanoski, J. A. N. Engl. J. Med. 2002,
346, 591; (b) Friedman, J. M. Nature 2000, 404, 632; (c)