Synthesis and SAR of heterocyclic carboxylic acid isosteres based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2010.03.028

SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.

Full text of DOI:10.1016/j.bmcl.2010.03.028

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2912–2915
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of heterocyclic carboxylic acid isosteres based on
2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for
the treatment of obesity
a
a
a
a
Mark Hadden a, , Allan Goodman , Cheng Guo , Peter R. Guzzo , Alan J. Henderson ,
Kevin Pattamana a, Megan Ruenz a, Bruce J. Sargent a, Brian Swenson a, Larry Yet a, Jian Liu b,
Shuwen He b, Iyassu K. Sebhat b, Linus S. Lin b, Constantin Tamvakopoulos e, Qianping Peng e,
Yanqing Kan c, Oksana Palyha c, Theresa M. Kelly c, Xiao-Ming Guan c, Joseph M. Metzger d,
Marc L. Reitman c, Ravi P. Nargund b
*
a AMRI, 26 Corporate Circle, Albany, NY 12212, USA
b Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
c Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
d Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
e Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented.
Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and
brain penetration are described.
Received 7 January 2010
Revised 3 March 2010
Accepted 5 March 2010
Available online 12 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
BRS-3
Obesity
Acid isosteres
According to the CDC’s Behavioral Risk Factor Surveillance Sys-
tem, over the past 20 years there has been a dramatic increase in
obesity in young adults in the United States, with only one state
having an obesity prevalence of less than 20%.1,2 This high rate of
occurrence combined with obesity being a risk factor in a wide
range of diseases3 such as type 2 diabetes, cardiovascular diseases
and cancer make it an important indication for pharmaceutical
intervention. Moreover, currently marketed drugs such as sibutr-
amine4 and orilstat5 have unsatisfactory efficacy and undesirable
side effects that limit their prescription amongst the general
population.
Bombesin receptor subtype-3 (BRS-3 or BB3), is an orphan G-
protein coupled receptor (GPCR) with high sequence identity to
BB1 and BB2 (ꢀ50%) and is located primarily in the hypothalamus
and testes.6 Preclinical validation of BRS-3’s role in energy homeo-
stasis has been demonstrated with genetically altered mice lacking
the BRS-3 receptor, causing induction of obesity, hypertension and
diabetes.7
Through a combination of high-throughput screening and SAR
development, a potent small molecule BRS-3 agonist 18 was dis-
covered (Fig. 1).
The carboxylic acid was mapped around the biphenyl ring
(structures not shown); however, all of these compounds lost po-
tency compared to 1. Interestingly, extending the acid moiety away
from the ring maintained good potency in compound 2 (Table 1).
Further SAR studies were pursued to improve oral bioavailabil-
ity and brain penetration whilst retaining binding and functional
agonism at the human BRS-3 receptor. Replacement of the carbox-
ylic acid group in compound 1 with traditional acid isosteres such
as tetrazole 1a and phenol 1b provided good binding and func-
HN
HN
N
N
COOH
O
CO2H
1
2
* Corresponding author. Tel.: +1 518 512 2835; fax: +1 518 512 2079.
E-mail address: mark.hadden@amriglobal.com (M. Hadden).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.028

M. Hadden et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2912–2915
2913
Table 1
The potency of BRS-3 agonists in human and mice BRS-3 receptors
Compound
HN
hBRS-3 binding IC50
,
hBRS-3 function EC50, nMa
(Activation%)b
mBRS-3 function EC50, nMa
(Activation%)b
Ar
R
nMa
N
R
Ar
1
11
15
31
25 (101)
56 (112)
133 (97)
9.6 (94)
16 (85)
34 (113)
COOH
N
N
1a
1b
HN
N
OH
S
1c
2
287
103
1767 (94)
54 (97)
NDc
NDc
O
N
H
O
O
O
CO2H
H
N
10a
10b
10c
6.1
22
27
41 (114)
172 (113)
78 (98)
5.8 (120)
NH
N
S
H
N
NDc
O
O
N
N
N
H
N
4.6 (115)
N
NH2
H
N
O
O
10d
10e
127
31
129 (89)
12 (122)
N
N
N
N
CF3
H
N
336 (107)
NDc
NH
O
H
N
11
12
5.3
83
30 (111)
399 (97)
2.9 (109)
NDc
O
O
N
N
H
N
N
N
14a
14b
See Scheme 3
See Scheme 3
N
10
20
29 (98)
56 (96)
11 (118)
27 (119)
OH
17
5.3
6.2
24 (100)
15 (100)
12 (111)
16 (119)
O
N
N
H
N
19a
N
N
(continued on next page)

2914
M. Hadden et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2912–2915
Table 1 (continued)
Compound
HN
hBRS-3 binding IC50
,
hBRS-3 function EC50, nMa
(Activation%)b
mBRS-3 function EC50, nMa
(Activation%)b
Ar
R
nMa
N
R
Ar
N
N
H
N
19b
26
18
42 (96)
13 (117)
13 (120)
N
N
24
42 (101)
NH
N
a
The reported data are the average of at least three repeated experiments.
The percentages of activation are the maxim activation of tested compounds relative to that of [
Not determined.
b
c
D
-Tyr6,b-Ala11,Phe13,Nle14]-Bombesin (6–14).
I
I
a
4a R=CO2t-Bu
4b R=CN
Tr
Tr
4c R=C
CH
OH
O
R
N
N
3
N
N
Tr
Tr
N
N
a
8
7
N
N
b
OMe
O
CN
O
O
B
6 R=CO2t-Bu
7 R=CN
NH
O
5
O
R
X
N
HN
N
N
b
9 X=Tr
10 X=H
c
H
c
6
N
2
O
N
O
CO2H
N
R
Scheme 1. Reagents and conditions: (a) BrCH2CO2t-Bu or BrCH2CN or propargyl
bromide, K2CO3, acetone, 91% (4a), 68% (4b), 99% (4c); (b) 4a or 4b, PdCl2(dppf),
Na2CO3, H2O, DMF, 80 °C, 16 h, 59% (6), 72% (7); (c) TFA, CH2Cl2, 91%.
Scheme 2. Reagents and conditions: (a) KOt-Bu, MeOH, 65 °C, 15 min, 100%; (b)
NH2NHC(S)NH2, 39% (R = SH, 9a); NH2NHC(O)H, 71%, (R = H, 9b); NH2NHC(NH)NH2,
19%, (R = NH2, 9c); NH2NH2, TFAA, pyridine, 59%, (R = CF3, 9d); NH2NHCO2Et, 69%,
(R = OH, 9e); (c) TFA, CH2Cl2.
tional responses at the human receptor and these results further
encouraged us to prepare a range of heterocyclic isosteres based
on compounds 1 and 2.
A convergent synthesis was adopted using key intermediate,
boronate ester 59 (Scheme 1). Alkylation of 2-iodophenol provided
the precursors 4a–c. Suzuki coupling of 4a and 4b with 5 yielded
intermediates 6 and 7. Double deprotection of 6 under acidic con-
ditions provided 2.
Electrophilic nitrile 7 was easily transformed into the corre-
sponding methylimidate 8 via reaction with alkoxide anion in meth-
anol.10 Reaction of this intermediate with an appropriately
substituted hydrazine, followed by removal of the trityl group with
TFA, provided rapid access to a range of heterocycles 10 (Scheme 2).
Alternatively, tetrazole 11 could be prepared via 1,3-dipolar
cycloaddition of nitrile 7 with sodium azide and ammonium chlo-
ride in DMF.11 1,2,3-Triazole 12 was prepared via addition of ben-
zylazide to 4c using Click chemistry12 followed by Suzuki coupling
with 5 and double deprotection (syntheses not shown).
Table 2
Total plasma and brain levelsa of BRS-3 agonists 1 h following IV dose in rats
Compd.
Dose (mg/kg)
Plasma (lM)
Brain (lM)
B/P ratio
10a
10c
11
14a
17
1
1
2
1
1
4.96
0.86
1.25
0.31
0.21
0.03
0.01
0.01
0.02
0.01
0.006
0.016
0.010
0.068
0.04
a
Data are averages of three repeated experiments.
Tr
N
HN
Of the range of heterocycles prepared, triazolothione 10a and
tetrazole 11 showed some of the best activity (hEC50 = 41, 30 nM,
respectively), indicating that isosteric replacement of the carbox-
ylic acid in 2 (hEC50 = 54 nM) was feasible. But unfortunately these
analogs failed to provide significant brain levels following intrave-
nous administration (Table 2). It was hoped that switching to the
less acidic aminotriazole 10c (pKa = 12.13)13 would help improve
brain penetration compared with 10a (pKa = 8.92) and 11
N
N
a, b, c
14a R=H
14b R=Me
13
CN
CO2Me
N
R
O
Scheme 3. Reagents and conditions: (a) NaBH4, CoCl2Á6H2O MeOH, 0 °C to 65 °C,
58%; (c) TFA, CH2Cl2, 78% (14a); (a) NaBH4, CoCl2Á6H2O MeOH, 0 °C to 65 °C, 47%; (b)
NaH, MeI, DMF, 71%; (c) TFA, CH2Cl2, 88% (14b).

M. Hadden et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2912–2915
2915
equally good potency at both the mouse and the human receptor
but failed to substantially increase brain levels. Heterocyclic ana-
logs of compound 17 (tetrazole 19a and triazole 19b) showed good
potency demonstrating the acid moiety in this series could also be
replaced by isosteres, but these compounds were not pursued
further due to low bioavailability in rat (F = 4.9% and 4.8%, respec-
tively). Constraining the heterocyclic system to form pyrazolopi-
peridine analog 24 (Scheme 5) maintained good binding and
functional potency and also significantly improved oral bioavail-
ability to 29%. Unfortunately this did not translate into improved
brain penetration. Further SAR studies which led to BRS-3 agonists
with improved CNS penetrating properties are reported in the pre-
vious Letter.9
R
Tr
N
N
N
a
c
N
N
N
Br
15
16 R=Tr
17 R=H
b
CO2H
Tr
HN
N
N
d or e
N
N
H
N
19a X=N
19b X=CH
18
CONH2
N
In summary, SAR studies were carried out around acids 1 and 2.
Replacement of the acid moiety with a range of isosteres main-
tained good in vitro potency. Despite improvements made in bio-
availability, significant increases in brain levels were not realized.
N
X
Scheme 4. Reagents and conditions: (a) CuI, K2CO3, (R)-pipecolinic acid, DMSO,
90 °C, 55%; (b) TFA, CH2Cl2; (c) NH3, EDC, HOBt, CH2Cl2, 66%; (d) (i) pyridine, TFAA,
dioxane, 50%; (ii) NaN3, NH4Cl, DMF, 100 °C, 8% (19a); (e) (i) Me2NCH(OEt)2, reflux;
(ii) AcOH, hydrazine, 90 °C, 24% (19b).
References and notes
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K.; Maeno, H.; Imaki, J.; Kikuyama, S.; Wada, E.; Wada, K. Nature 1997, 390, 165.
8. He, S.; Dobbelaar, P. H.; Liu, J.; Jian, T.; Sebhat, I. K.; Lin, L. S.; Goodman, A.; Guo,
C.; Guzzo, P. R.; Hadden, M.; Henderson, A. J.; Ruenz, M.; Sargent, B. J.; Yet, L.;
Kelly, T. M.; Palyha, O.; Kan, Y.; Pan, J.; Chen, H.; Marsh, D. J.; Shearman, L. P.;
Strack, A. M.; Metzger, J. M.; Feighner, S. D.; Tan, C.; Howard, A. D.;
Tamvakopoulos, C.; Peng, Q.; Guan, X.; Reitman, M. L.; Patchett, A. A.;
Wyvratt, M. J.; Nargund, N. P. Bioorg. Med. Chem. Lett. 2009. ‘Discovery of
substituted biphenyl imidazoles as potent, bioavailable bombesin receptor
subtype-3 agonists’ accompanying manuscript.
9. Liu, J.; He, S. H.; Jian, T.; Dobbelaar, P.; Sebhat, I. K.; Lin, L. S.; Goodman, A.; Guo,
C.; Guzzo, P. R.; Hadden, M.; Henderson, A. J.; Ruenz, M.; Pattamana, K.;
Sargent, B. J.; Swenson, B.; Yet, L.; Tamvakopoulos, C.; Kelly, T. M.; Peng, Q.;
Kan, Y.; Pan, J.; Palyha, O.; Marsh, D. J.; Shearman, L. P.; Strack, A. M.; Metzger, J.
M.; Howard, A. D.; Guan, X.; Reitman, M. L.; Wyvratt, M. J.; Nargund, N. P.
Bioorg. Med. Chem. Lett. 2009. ‘Synthesis and SAR of derivatives based on 2-
biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the
treatment of obesity’ accompanying manuscript.
10. Poonian, M. S.; Nowowsiat, E. F. J. Org. Chem. 1980, 45, 203.
11. Tilley, J. W.; Danho, W.; Lovey, K.; Wagner, R.; Swistok, J.; Makofske, R.;
Michalewsky, J.; Triscari, J.; Nelson, D.; Weatherford, S. J. Med. Chem. 1991, 34,
1125.
12. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596.
13. pKa’s were calculated online using the Marvin calculator from Chemaxon.
14. Dobson, P. D.; Kell, D. B. Nat. Rev. Drug Discovery 2008, 7, 205.
15. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
16. Pipecolic acid has been shown to be actively transported into mouse brain;
Kim, J. S.; Giacobini, E. Dev. Brain Res. 1985, 22, 181.
a
b
c
N
N
N
SEM
SEM
N
H
N
N
N
N
N
H
20
21
22
R
N
HN
N
N
d
N
N
N
NH
23
24
SEM
N
N
Scheme 5. Reagents and conditions: (a) NaH, SEM-Cl, DMF, 64%; (b) Pd/C, H2, EtOH,
68%; (c) 15, Pd(OAc)2, KOt-Bu, dicyclohexylbiphenylphosphine, toluene, 150 °C,
microwaves, 32%; (d) TFA, H2O, 60 °C, 59%.
(pKa = 4.58). Although functional activity was maintained
(hEC50 = 78 nM, 98%) no in increase B/P ratio was seen.
In an effort to reduce rotatable bonds to help improve brain
penetration verses unconstrained analogs, constrained lactams
14a and 14b were synthesized (Scheme 3). Good agonist functional
potency was observed with 14a (hEC50 = 29 nM, 98%). Surprisingly
compound 14b, in which the H-bond donor was replaced with a
methyl group, also showed good activity (hEC50 = 56 nM, 96%).
However no improvement in brain concentration was observed
with these analogs.
In an attempt to use an active transport mechanism such as an
amino acid transporter14 to improve brain penetration, amino acid
17 was prepared via a copper mediated15 coupling of bromide 15
with (R)-pipecolic acid16 (Scheme 4). This compound exhibited