Discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 agonists and their unusual chirality

Article abstract of DOI:10.1021/ml200207w

We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.

Full text of DOI:10.1021/ml200207w

LETTER
pubs.acs.org/acsmedchemlett
Discovery of Benzodiazepine Sulfonamide-Based Bombesin Receptor
Subtype 3 Agonists and Their Unusual Chirality
Ping Liu,*,† Thomas J. Lanza, Jr.,† Marc Chioda,† Carrie Jones,† Harry R. Chobanian,† Yan Guo,†
Linda Chang,† Theresa M. Kelly,‡ Yanqing Kan,‡ Oksana Palyha,‡ Xiao-Ming Guan,‡ Donald J. Marsh,‡
Joseph M. Metzger,§ Katie Ramsay,§ Sheng-Ping Wang,§ Alison M. Strack,§ Randy Miller,|| Jianmei Pang,||
Kathy Lyons,|| Jasminka Dragovic,|| Jian G. Ning,^ Wes A. Schafer,^ Christopher J. Welch,^ Xiaoyi Gong,^
Ying-Duo Gao,# Viktor Hornak,# Richard G. Ball,r Nancy Tsou,r Marc L. Reitman,‡
Matthew J. Wyvratt,† Ravi P. Nargund,† and Linus S. Lin†
Departments of †Medicinal Chemistry, ‡Metabolic Disorders, §Pharmacology, Drug Metabolism, ^Analytic Chemistry, #Chemistry
Modeling & Informatics, and rProcess Research, Merck Research Laboratories, Rahway, New Jersey 07065, United States
S Supporting Information
b
ABSTRACT: We report herein the discovery of benzodiazepine sulfonamide-based bom-
besin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-
throughput screening lead, we prepared a series of BRS-3 agonists with improved potency
and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-
dependent food intake reduction and body weight loss after oral dosing in diet-induced obese
mice. This effort also led to the discovery of a novel family of chiral molecules originated from
the conformationally constrained seven-membered diazepine ring.
KEYWORDS: Bombesinreceptorsubtype3, BRS-3,agonist, obesity, benzodiazepinesulfonamide,
planar chirality, atropisomerism
besity is a serious and chronic medical condition that has
become a major global health issue. In the United States,
Our efforts started with a high-throughput screening lead (1)
as shown in Figure 1. This lead exhibited moderate BRS-3
potency in human and mouse and poor pharmacokinetic proper-
ties in the rat (Clp = 164 mL/min/kg, F = 1%, t1/2 = 1.6 h). Our
initial aim was to determine whether the diazepine core was
optimal. A systematic core structure modification was under-
taken, which included moving the pyridine N, breaking the
diazepine ring, and saturating the left-hand side phenyl ring.
Each case resulted in complete loss of potency. Therefore, the
diazepine core was preserved for further structureꢀactivity
relationship (SAR) studies that focused on varying the substit-
uents of the aromatic rings.
The synthesis of the diazepine sulfonamide analogues was
straightforward (Scheme 1). Condensation of substituted phe-
nyldiamine 2 and 2-chloronicotinic acid 3 under microwave or
thermal conditions provided a regioisomeric mixture of 4 and 5,
favoring the desired isomer 4 in a ratio of 3:1 to 9:1. This mixture
was reduced by borane to diazepine 6, which upon reacting with
the sulfonyl chloride afforded diazepine sulfonamide 8. Typically,
the undesired regioisomer was carried on to the final step where 7
was separated from 8 by silica gel chromatography.
O
obesity rates for adults have doubled, and rates for children have
tripled over the last 30 years. Currently, around one-third of U.S.
adults and 16% of U.S. children are considered obese.1 In many
cases, excessive body weight is the root cause of subsequent
comorbidities, including type 2 diabetes, hypertension, cardio-
vascular disease, cancer, and arthritis.2 The preferred approach to
manage obesity calls for lifestyle changes including control of
calorie intake and increase in physical activities. However, this
approach alone is often insufficient or unsustainable. In the
United States, orlistat3 is the only drug approved for the
treatment of obesity and has suboptimal tolerability and limited
efficacy (the other obesity drug, sibutramine, was recently with-
drawn from the market by Abbott Laboratories4). Therefore,
new antiobesity agents are highly desirable. Our laboratories are
interested in pursuing new mechanisms for the treatment of
obesity. The involvement of the bombesin receptor subtype-3
(BRS-3) in regulating energy homeostasis has been demon-
strated in animal models. Mice lacking functional BRS-3 develop
metabolic defects and obesity.5,6 On the other hand, a BRS-3
agonist caused food intake reduction and an increase in meta-
bolic rate in established diet-induced obese (eDIO) mice,
suggesting that the BRS-3 receptor may serve as a potential
target for treating obesity.7 Recently, medicinal chemistry efforts
to identify small molecule BRS-3 agonists have been reported by
others8,9 and our laboratories.10ꢀ14 In this letter, we describe our
continued efforts in this area that led to the discovery of a novel
class of BRS-3 agonists.
However, both silica gel chromatography and reverse-phase high-
performance liquid chromatography (HPLC) failed to provide an
acceptable separation of 7a from 8. Then, we subjected the mixture
to a ChiralCel OD column, expecting two peaks corresponding to
Received: August 23, 2011
Accepted: October 3, 2011
Published: October 03, 2011
r
2011 American Chemical Society
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LETTER
Figure 3. X-ray analysis revealed planar chirality.17
Figure 1. Structures of orlistat, sibutramine, and HTS lead 1.
Scheme 1a
Figure 4. “SAR” of the atropisomerism. RA = H (8k) or F (8l), no
atropisomerism; 9 did not exhibit atropisomerism. If RA > F, 8 exhibited
atropisomerism, e.g., 8i (RA = Cl), 8m (RA = OH), and 10.
regioisomer 7a, the two compounds obtained corresponding to the
other two peaks displayed exactly the same 1H NMR but opposite
rotation (8a, [α]D = ꢀ157ꢀ; 8b, [α]D = +155ꢀ), suggesting an
enantiomeric pair (Figure 2). Because the molecule does not
possess a chiral center, possible causes for the observed
atropisomerism15 include hindered inversion of the sulfonamide
nitrogen, restricted rotation about the NꢀS single bond, and
conformationally constrained seven-membered diazepine ring sys-
tem. On the basis of X-ray analysis of 8a and 8b, the bond distances
from the sulfonamide N to the connected atoms are all typical for
single-bond lengths, but the geometry around this N is almost planar
(Figure 3). Both molecular modeling and X-ray analysis revealed
that no obvious energy barrier existed for either the NꢀS bond
rotation or the inversion of the nearly planar sulfonamide nitrogen.
In contrast, the puckered diazepine ring was highly conformationally
constrained, and a ring flip would place the sulfonyl group and the
7-Me substituent of the phenyl ring in the same plane, resulting in
severe van der Waals interactions between these groups. Modeling
suggested a barrier of ∼33 kcal/mol for the ring interconversion.
Chiral LC study of 8b afforded a first-order kinetics with a rate
constant of 1.35 ꢁ 10ꢀ8 sꢀ1 at 25 ꢀC and 1.03 ꢁ 10ꢀ7 sꢀ1 at 40 ꢀC,
corresponding to activation energy of 25.2 kcal/mol. Although the
racemization is slow at <50 ꢀC (t1/2 = 296 days at 25 ꢀC; 39 days at
40 ꢀC), the rate of interconversion is significantly higher at >100 ꢀC,
and a complete racemization was observed after 4 h at 100 ꢀC.16
The “SAR” of the atropisomerism is consistent with the planar
chirality where the steric hindrance between the sulfonyl group
and the neighboring substituent RA on the Ph ring accounted for
the interconversion barrier (Figure 4). The atropoisomers of the
7-H and 7-F analogues were not separable by HPLC at room
temperature, neither was compound 9 with only an electron lone
a Reagents and conditions: (a) 2-Butoxyethanol, microwave 180ꢀ220 ꢀC,
15 min to 1 h; or thermoheating, 150 ꢀC, 4ꢀ6 h. (b) BH3 THF.
3
(c) CH2Cl2, pyr.
Figure 2. Discovery of the atropisomerism.
the two regioisomers. To our surprise, three peaks were present in
the HPLC trace. While one peak corresponded to the undesired
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LETTER
Table 1. Substitution Effects on the Human and Mouse BRS-3 Activity
compda
substitution
7-Me, 8-Me
hBRS-3b IC50 (nM)
hBRS-3b EC50 (nM) (%Act)c
mBRS-3b EC50 (nM) (% Act)c
1
40 ( 21
325 ( 117 (91 ( 9%)
>10000d
248 ( 42 (101 ( 3%)
>10000d
7a
9-Me, 10-Me
80% inhd at 10 μM
1.4 ( 0.9
169 ( 139
10 ( 4.5
8a (S)
8b (R)
8c
7-Me, 8-Me, 2-CF3
7-Me, 8-Me, 2-CF3
7-Me, 8-Me, 2-Me
7-Me, 8-Me, 2-CN
7-Me, 8-Me, 2-Cl
7-Me, 8-Me, 3-Cl
7-Me, 8-Me, 2-Cl, 3-F
7-Me, 2-CF3
97 ( 23 (96 ( 10%)
>10000
33 ( 11 (98 ( 7%)
>10000
131 ( 36 (92 ( 13%)
50 ( 8 (100 ( 4%)
38 ( 9 (97 ( 2%)
>10000d
232 ( 50 (107 ( 10%)
50 ( 3 (103 ( 1%)
98 ( 25 (105 ( 7%)
>10000d
8d (S)
8e (S)
8f
4.4 ( 1.0
1.2 ( 0.3
430 ( 170
8.9 ( 3.0
0.9 ( 0.1
3.2 ( 0.5
5.8 ( 0.1
5.5 ( 0.5
5.0 ( 0.3
2.2 ( 0.4
5.3 ( 0.2
0.7 ( 0.1
8g
277 ( 80 (83 ( 1%)
50 ( 14 (101 ( 10%)
63 ( 33 (96 ( 6%)
199 ( 34 (83 ( 11%)
110 ( 23 (96 ( 10%)
77 ( 10 (96 ( 2%)
88 ( 21 (103 ( 1%)
110 ( 27 (104 ( 0%)
108 ( 44 (101 ( 8%)
371 ( 13 (82 ( 6%)
120 ( 14 (106 ( 1%)
155 ( 53 (100 ( 13%)
377 ( 7 (82 ( 4%)
161 ( 11 (98 ( 7%)
134 ( 14 (97 ( 0%)
209 ( 62 (115 ( 14%)
171 ( 5 (112 ( 12%)
129 ( 18 (107 ( 4%)
8h (S)
8i (S)
8j
7-Cl, 2-CF3
8-Me, 2-CF3
8k
2-CF3
8l
7-F, 2-CF3, 8-C(CH3)2OH
7-OH, 2-CF3
8m (S)
9
see Figure 4
10 (S)
see Figure 4
a Racemic mixture or achiral compound (7, 8j, 8k, etc.), except as noted. b Data expressed as mean ( SD (n g 2 independent experiments). c % Act
represents the maximum activation of tested compound relative to that of the dY peptide ([D-Tyr,7β-Ala,17 Phe,19 and Nle20]-bombesin(6ꢀ14)).
d Assayed only once.
pair on RA position. Not surprisingly, fused ring analogue 10
exhibited atropisomerism, and the two enantiomers were readily
separated.
as thiazole (11g) and thiophene analogues (11h and 11i), also
exhibited reasonable BRS-3 potency.
A number of more potent BRS-3 agonists were evaluated for
their pharmacokinetic properties, and several displayed an im-
proved PK profile (Table 3). As compared to the initial lead 1,
these compounds demonstrated lower clearance and higher oral
AUC and bioavailability in the rat. The pharmacokinetic proper-
ties of 8a were also evaluated in the rhesus monkey where the
bioavailability was 17% and the half-life was 1.8 h.
Compound 8a exhibited excellent potency against dog and
rhesus BRS-3 receptors: dog IC50 = 1.6 nM, EC50 = 36 nM,
97% Act; rhesus IC50 = 3.0 nM, EC50 = 70 nM, 97% Act. This
compound was screened against >100 receptors, ion channels,
and enzymes; seven off-targets were identified with IC50
values in the range of 1ꢀ10 μM, but none was considered
significant. Compound 8a was very selective over the two key
ion channels, hERG IC50 > 10 μM and DLZ IC50 > 10 μM, but
was a potent activator of human PXR (EC50 = 678 nM; 42%
Act at 10 μM).20
Compound 8a was assessed for acute efficacy in wild-type
(WT) and BRS-3 KO mice. In WT mice, the compound caused
significant food intake reduction and body weight loss, in a dose-
dependent manner at 3 and 30 mpk 18 h after oral dosing. In KO
mice, no effect was observed at 3 and 30 mpk. After subchronic
dosing (20 mpk, BID) in e-DIO mice, the compound caused
5.2% body weight loss on day 4 (Figure 5).21 The body weight
loss was caused by reduction in food intake as well as increase in
fasting metabolic rate.22
As expected, the two atropisomers, 8a and 8b, behaved very
differently toward the BRS-3 receptors. The (S)-isomer 8a
exhibited hBRS-3 IC50 of 1.4 nM (125I-dY-peptide was used as
a radioligand in the binding assay) and EC50 of 97 nM, over
100-fold more potent than the (R)-isomer 8b (Table 1).18 As
compared to initial lead 1, CF3 at the 2-position (8a) im-
proved hBRS-3 binding affinity by 30-fold and mouse func-
tional activity by 8-fold. While the 2-position tolerated a
variety of functionalities, such as methyl (8c), cyano (8d),
and chloro (8e), the 3-position preferred no substituents (8f
vs 1; 8g vs 8e). For the left-hand side aromatic ring, deletion of
8-methyl (8h) slightly improved potency; however, removal
of 7-methyl (8j) or both methyls (8k) decreased potency.
Replacing the 7-methyl group with chloro (8i), fluoro (8l), or
hydroxyl (8m) resulted in comparable potency. The fused ring
analogue 10 was among the most potent compounds with
hBRS-3 IC50 of 0.7 nM.
Next, the SAR of the aryl sulfonyl group was explored.19
Analogues 11aꢀi in Table 2 were synthesized as described
in Scheme 1 using the appropriate sulfonyl chloride. para-
Substituted phenyl was preferred, and a variety of substituents
were tolerated. While isopropyl (11a) and trifluoromethoxy
(11d) groups could serve as replacements for the tert-butyl
(8a), the methylsulfonyl group (11c) caused loss of potency.
In addition to phenyl analogues, heterocyclic analogues, such
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ACS Medicinal Chemistry Letters
LETTER
Table 2. Human and Mouse BRS-3 Activity of 11
Figure 5. Effect of 8a on subchronic body weight of eDIO mice.
properties, of which compound 8a caused mechanism-based,
dose-dependent food intake reduction and body weight loss
after oral dosing in eDIO mice.
’ ASSOCIATED CONTENT
S
Supporting Information. Synthetic procedures and ana-
b
lytical data of selected BRS-3 agonists, conditions for all of the
biological assays, and X-ray, chiral LC, and modeling methods.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 732-594-0321. Fax: 732-594-9556. E-mail: ping_liu2@
merck.com.
a Racemic mixture, except as noted. b Data expressed as mean ( SD (n g
2 independent experiments). c % Act represents the maximum activation
of tested compound relative to that of the dY peptide.
’ ACKNOWLEDGMENT
We thank Dr. Timothy A. Blizzard for helpful discussions and
the Department of Laboratory Animal Resources for their
assistance in animal dosing and sampling.
Table 3. Rata Pharmacokinetic Datab of Selected
Compounds
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(18) There was a discrepancy between IC50 and EC50 because of the
kinetic effects associated with the EC50 assay. For example, when 8a was
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