Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents

Article abstract of DOI:10.1016/j.bmcl.2017.12.051

A series of novel carbazole-containing amides and ureas were synthesized. A structure–activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.

Full text of DOI:10.1016/j.bmcl.2017.12.051

Accepted Manuscript
Carbazole-containing amides and ureas: Discovery of cryptochrome modulators
as antihyperglycemic agents
Paul S. Humphries, Ross Bersot, John Kincaid, Eric Mabery, Kerryn McCluskie,
Timothy Park, Travis Renner, Erin Riegler, Tod Steinfeld, Eric D. Turtle, Zhi-
Liang Wei, Erik Willis
PII:
S0960-894X(17)31225-8
https://doi.org/10.1016/j.bmcl.2017.12.051
BMCL 25507
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 November 2017
21 December 2017
22 December 2017
Please cite this article as: Humphries, P.S., Bersot, R., Kincaid, J., Mabery, E., McCluskie, K., Park, T., Renner, T.,
Riegler, E., Steinfeld, T., Turtle, E.D., Wei, Z-L., Willis, E., Carbazole-containing amides and ureas: Discovery of
cryptochrome modulators as antihyperglycemic agents, Bioorganic & Medicinal Chemistry Letters (2017), doi:
https://doi.org/10.1016/j.bmcl.2017.12.051
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Graphical Abstract
Carbazole-containing amides and ureas:
Discovery of cryptochrome modulators as
antihyperglycemic agents
Leave this area blank for abstract info.
Paul S. Humphries,a,* Ross Bersot,a John Kincaid,b Eric Mabery,a Kerryn McCluskie,a Timothy Park,a Travis
Renner,a Erin Riegler,a Tod Steinfeld,a Eric D. Turtle,a Zhi-Liang Wei,b and Erik Willis a

Bioorganic & Medicinal Chemistry Letters
Carbazole-containing amides and ureas: Discovery of cryptochrome modulators
as antihyperglycemic agents
Paul S. Humphries, a, Ross Bersot,a John Kincaid,b Eric Mabery,a Kerryn McCluskie,a Timothy Park,a
Travis Renner,a Erin Riegler,a Tod Steinfeld,a Eric D. Turtle,a Zhi-Liang Wei,b and Erik Willis a
aReset Therapeutics, 260 Littlefield Avenue, Suite 200, South San Francisco, CA 94080, USA
bSynterys, 29540 Kohoutek Way, Union City, CA 94587, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity
relationship study of these compounds led to the identification of potent cryptochrome
modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results
of efficacy studies in db/db mice, compound 50 was selected for further profiling.
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Cryptochrome; Circadian; Diabetes; Carbazole; SAR
———
 Corresponding author. Tel.: +1-650-235-4131; e-mail: paul@resettherapeutics.com

Type 2 diabetes (T2D) is a metabolic disorder that accounts
for 422 million patients worldwide and the number is likely to
grow to greater than 590 million by the year 2035.1 T2D is a
major cause of blindness, kidney failure, heart attacks, stroke and
lower limb amputation.2,3
further determine the structural requirements for activity and to
increase in vivo exposure, we wished to synthesize compounds
represented by the general structure 2 (Fig. 1). Herein, we report
the synthesis, structure-activity relationships (SAR), and in vivo
activity of this new class of compounds.31
In mammals, many physiological processes such as body
temperature, hormone secretion, metabolism, and sleep/wake
behavior are controlled by the circadian clock in a daily rhythmic
manner.4-7 Dysregulation in the circadian system caused by
variants of clock genes has been correlated with T2D and insulin
resistance.8,9 More specifically, genetic variants in Cryptochrome
(Cry) genes have been linked with glucose homeostasis, hepatic
lipid content and beta-cell function.10-15
Figure 1. KL001, initial lead 1 and new lead scaffold 2.
Following the early optimization to cyclic sulfonamide 1,
installation of fluorine substituents at the 3- and 6- positions of
the carbazole moiety was shown to decrease in vitro intrinsic
clearance without affecting potency and so this moiety was held
constant going forward.
The synthetic route for the preparation of critical epoxide
intermediate 6 is shown in Scheme 1. Coupling of 2-chloro-4-
fluoroaniline 3 and 1-bromo-4-fluorobenzene afforded 4 in high
yield and purity. This crude material was telescoped directly into
the intramolecular direct arylation and yielded the desired
carbazole 5 in a 64% yield over two steps. Coupling of
epibromohydrin and carbazole 5 afforded epoxide 6 in excellent
Cell-autonomous circadian rhythms are generated through
clock genes, which are orchestrated by interconnected
transcriptional and translational regulatory loops. The core clock
loop is constituted by two transcriptional activators, CLOCK and
BMAL1, and two repressors: Cryptochrome (CRY1 and CRY2)
and Period (PER1 and PER2). The CLOCK–BMAL1
heterodimer activates the transcription of Cry and Per though
binding to E-box enhancer elements. Translated PER and CRY
proteins dimerize and translocate into the nucleus to inhibit
CLOCK–BMAL1 function, resulting in rhythmic gene
expression pattern. The loop regulates a large number of clock-
controlled genes in circadian physiology. This timing mechanism
is regulated by post-translational modifications such as
phosphorylation and ubiquitination, which tune the pace of the
clock.16,17 The SCFFBXL3 ubiquitin ligase complex plays an
important role in CRY ubiquitination and degradation to
modulate the negative feedback loop.18-20 Recent X-ray
crystallographic results revealed details of CRY regulation by its
PER partners and stability by FBXL3. The F-box protein FBXL3
occupies the FAD binding pocket of CRY2 with its C-terminal
tail and also covers the PER binding domain of CRY2.21,22
Circadian clock-deficient animals have been utilized to
examine disease pathophysiology linked to the circadian clock.
Mice lacking Cry1 and Cry2 (Cry-null mice), on a high fat diet,
rapidly gain weight, become hyperinsulinemic and have elevated
corticosterone and upregulated expression of lipogenic genes in
white adipose tissue.23 These mice also display a rapid
progression from non-alcoholic fatty liver disease to non-
alcoholic steatohepatitis, fibrosis and hepatocellular carcinoma.24
Cry-null mice exhibit salt-sensitive hypertension due to
abnormally high synthesis of the mineralocorticoid aldosterone
by the adrenal gland.25-26 Under normal salt exposure, mice show
increased albumin excretion and kidney tubular injury, decreased
nephrin expression and increased reactive oxygen species
production in the absence of hypertension.27
yield.
Scheme 1. Reagents and conditions: (a) 4-F-PhBr, Pd2(dba)3, PtBu3·HBF4,
KOtBu, PhMe, 50 ºC, 3 h; (b) Pd(OAc)2, PCy3·HBF4, K2CO3, DMA, 130 ºC,
7 h, 64% over two steps; (c) epibromohydrin, KOH, DMF, 0 ºC to rt, 16 h,
90%.
Lactams of various ring sizes and substitutions were
produced by the synthetic route in Scheme 2. Commercially
available benzyl-protected lactams 7 were deprotonated with base
and then treated with a variety of alkyl halides to afford
substituted lactams 8. Deprotection of 8 yielded 9, which were
then treated with sodium hydride and epoxide 6 to produce final
products 10-23. Repeating the deprotonation and alkylation step
(e.g. transformation of 7 to 8) on compound 8, followed by
deprotection and coupling with epoxide 6 afforded final products
31-34. Final products 24-47 were synthesized by coupling
commercially available or previously reported lactams with
A period-lengthening small molecule, KL001, that directly
targets CRY was discovered (Fig. 1)28 to stabilize CRY by
binding to the FAD-binding pocket in competition with
FBXL3,29 thereby extending the observed circadian period.
KL001 was initially optimized to yield 1, which demonstrated
antihyperglycemic effects in animal models of T2D.30 In order to

epoxide 6.
carbonyldiimidazole (CDI) yielded the final products 50-65.
Scheme 2. Reagents and conditions: (a) LDA, THF, -78 ºC, 30 min then R-
Hal, -78 ºC to rt, 16 h; (b) TfOH, PhMe, µW, 200 ºC, 15 min to 1 h; (c) NaH,
DMF, rt then 6, 45 ºC, 16 h.
Scheme 3. Reagents and conditions: (a) 6, EtOH, 40 ºC, 16 h; (b) CDI, THF,
0 ºC to rt, 16 h.
The newly synthesized compounds were evaluated for their
effects on circadian rhythms in a human osteosarcoma U2OS cell
line harboring a Per2-dLuc luciferase reporter.28 Continuous
incubation with these compounds causes period lengthening and
amplitude reduction in a dose-dependent manner. The amplitude
effect of these derivatives was analyzed by testing 8 points of
threefold dilution series to obtain EC50 values. Lipophilic
efficiency (LipE) was calculated in an effort to move towards a
quality drug candidate with high potency, low dose and an
adequate safety profile. LipE is a parameter used in drug design
to evaluate the quality of compounds, linking potency and
lipophilicity in an attempt to estimate drug likeness.32-34
A variety of commercially available or previously reported
cyclic carbamates and bicyclic amides were also coupled with
epoxide 6 to afford final products 35-47.
Attempts to further decrease lipophilicity led us to explore the
tolerance and SAR for substituted ureas on the right-hand side of
the chemical series. As shown in Scheme 3, commercially
available diamines 48 were coupled with epoxide 6 to afford
intermediates 49. Cyclization of intermediates 49 with
Table 1. In vitro activities of amides 10-34
Compound
n
N/A
1
R
Per2 EC50 (µM)a
0.870
LipEb
3.85
3.76
3.83
3.39
2.51
2.95
2.61
2.87
2.94
2.19
1.70
4.29
4.19
Compound
n
1
2
1
2
1
1
2
2
2
1
2
1
2
R
Per2 EC50 (µM)a
0.855
LipEb
3.93
3.82
3.18
3.72
3.78
3.84
3.40
3.95
2.96
2.95
3.44
3.24
2.35
KL001
10
N/A
H
22
23
24
25
26
27
28
29
30
31
32
33
34
3-OMe
3-OMe
4-Me
0.625
0.330
11
2
H
0.192
1.033
12
1
3-Me
3-Me
3-Et
3-Et
3-iPr
3-iPr
3-Ph
3-Ph
3-F
0.424
4-Me
0.128
13
2
1.153
4-OMe
5-Me
1.138
14
1
0.417
0.199
15
2
0.332
5-Me
0.224
16
1
0.261
5-OMe
6-Me
0.397
17
2
0.079
0.541
18
1
0.487
3-di-F
3-di-F
3-di-Me
3-di-Me
0.716
19
2
0.547
0.194
20
1
0.208
0.164
21
2
3-F
0.079
0.463
a
Per2 activities were measured in human U2OS cells harboring a Per2-dluc luciferase reporter analogous to published procedures.29 The EC50 refers to the
concentration at which 50% of a given compounds’ intrinsic maximal response has been reached.
b LipE = pEC50 – cLogP. cLogP calculated within CDD Vault utilizing ChemAxon’s fragment-based approach.
Table 2. In vitro activities of compounds 35-47
Compound
Structure
Per2 EC50 (µM)
9.768
LipE
2.35
Compound
Structure
Per2 EC50 (µM)
0.163
LipE
3.77
35
42

36
4.981
2.58
43
1.487
2.01
37
38
39
0.447
0.246
0.167
4.48
4.17
3.97
44
45
46
3.732
1.361
1.69
1.76
1.02
15.222
40
41
0.149
0.565
4.20
3.41
47
7.428
0.95

Table 3. In vitro activities of ureas 50-65
Compound
n
N/A
1
R1
N/A
H
R2
N/A
H
Per2 EC50 (µM)
0.870
LipE
3.85
4.51
4.73
4.23
3.93
3.46
3.73
3.29
3.22
Compound
n
1
2
1
2
1
2
2
2
R1
H
R2
3-Ph
3-Ph
H
Per2 EC50 (µM)
0.528
LipE
2.46
2.89
3.83
3.75
3.58
3.38
4.00
3.72
KL001
50
58
59
60
61
62
63
64
65
0.363
H
0.171
51
2
H
H
0.188
4-Me
4-Me
5-Me
5-Me
5-OMe
6-Me
0.667
52
1
H
3-Me
3-Me
3-Et
3-Et
3-iPr
3-iPr
0.406
H
0.417
53
2
H
0.719
H
1.186
54
1
H
1.059
H
0.833
55
2
H
0.497
H
1.121
56
1
H
0.605
H
0.742
57
2
H
0.620
Initially, we investigated the impact of moving from cyclic
sulfonamides (e.g. 1) to lactams and to explore the effects of
varying substitutions around the ring, Table 1. Per2 potency for
compounds 10-34 demonstrate that large changes in this region
can be accommodated. In general, 6-membered lactams are more
potent than their 5-membered counterparts although their LipE
values are comparable (e.g. compound 10 vs 11). Substitution at
the 3-position is well tolerated with fluorine being the optimal for
both Per2 potency and lipophilic efficiency (e.g. compound 20 vs
10). Unfortunately, substitution at the 4-, 5- or 6-position offers
no improvement in potency and LipE vs their unsubstituted
counterparts (e.g. compounds 25, 28 and 30 vs 11). Finally,
double substitution at the 3-position did not provide any further
enhancement in Per2 potency and LipE (e.g. compounds 31 and
33 vs 20 and 12).
adipose, brown adipose and skeletal muscle) at multiple
timepoints (1 h, 4 h, 8 h, 12 h and 24 h) to evaluate compound
exposure and gene expression.38 Compound 50 was shown to
have the optimal combination of peripheral metabolic tissue
exposure and circadian clock modulation (data not shown).
Compound 50 was then progressed through a panel of screens to
assess off target pharmacology (Eurofins ExpresSProfile) and
showed no significant activity ≤10 µM, no activity at the hERG
channel, and no in vitro genotoxicity in micronucleus and Ames
assays.
Compound 50 was then evaluated in a db/db mouse model of
diabetes (Fig. 2).35 Treatment of male db/db mice (8 wks of age)
with compound 50 (10-100 mg/kg, q.d., PO for 7 days)
significantly enhanced glucose clearance at 100 mg/kg (39%
AUC reduction; p ≤ 0.001) in an oral glucose tolerance test in a
dose-dependent manner. Compound 50 also caused a 14%
In an effort to introduce more polarity, installation of an
oxygen atom into the lactam ring was attempted, Table 2. Cyclic
carbamates (e.g. compounds 35 and 36) were not tolerated and a
large decrease in Per2 potency was observed. Pleasingly, moving
to a morpholinone ring resulted in only a minor loss of potency
and retention of lipophilic efficiency (e.g compound 37 vs 11). A
variety of bicylic lactams were then examined, Table 2.
Azabicyclohexanones and azabicycloheptanones were all well
tolerated as shown by compounds 38-42. The majority of these
compounds exhibited good potency and LipE. Unfortunately,
aromatic-containing bicyclic lactams 43-47 all exhibited large
reductions in Per2 potency thus displaying the limits to
substituent tolerance for this region of the chemical series.
Further efforts to lower lipophilicity led us to explore the
tolerance for moving to cyclic ureas and to investigate the effects
of varying substitutions around the ring, Table 3. Per2 potency
for compounds 50-65 demonstrate that large changes in this
region can be tolerated. Once again, in general, 6-membered
ureas are more potent than their 5-membered counterparts
although their LipE values are similar (e.g. compound 50 vs 51).
Substitution at the 3-position is well tolerated although the
unsubstituted ureas proved optimal for both Per2 potency and
lipophilic efficiency (e.g. compound 52 vs 50). Unfortunately,
substitution at the 4-, 5- or 6-position offers no improvement in
potency and LipE vs their unsubstituted counterparts (e.g.
compounds 60, 62, 64 and 65 vs 50).
reduction in fasting blood glucose at 100 mg/kg (data not
shown).
Figure 2. Compound 50 reduces glucose intolerance in obese, insulin-
resistant mice.
In summary, we have identified a novel class of carbazole-
containing amides and ureas as potent cryptochrome modulators.
Systematic SAR studies generated a multitude of potent
compounds with improved lipophilic efficiency and in vivo
exposure. Compound 50 represents an improved small molecule
cryptochrome modulator with the potential to treat metabolic
disorders including type 2 diabetes.
Select compounds with adequate Per2 potency and LipE were
then submitted to an in vitro ADME panel (intrinsic clearance,
permeability and kinetic solubility). Based on the results of this
exercise (data not shown), compounds 10, 11, 20, 21, 42, 50 and
51 were then selected for mouse pharmacokinetic/
pharmacodynamic (PK/PD) studies. Male db/db mice (8 wks of
age) were treated with one dose of each compound (30 mg/kg,
PO) followed by collection of plasma and tissues (liver, white
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