2848
H. R. Chobanian et al. / Bioorg. Med. Chem. 20 (2012) 2845–2849
Table 2
of a potency boost. The secondary amide 12a also showed excellent
in vitro potency across species making it a viable candidate for fur-
ther profiling.
Rat PK data for BRS-3 agonists14
Compound Clp (mL/min/kg) T1/2 (h) PO AUCN
(
lM h kg/mg) Foral (%)
These exciting in vitro results prompted a comparative PK study
of 11a, 11b, 12a–c, and MK-7725 (Table 2). One can surmise that
the linker in compounds 11a and 11b seems to cut the half-life
by ꢀfourfold, however the exposure and bioavailability remain
excellent in only the case of compound 11a. Compound 11b has
MK-7725
11a
11b
12a
12b
16
12
21
33
31
25
11
3.1
2.9
1.6
0.8
1.7
1.60
2.60
0.60
0.30
0.30
0.69
93
100
49
31
32
12c
60
lower oral exposure (0.60 lM h kg/mg) and comparatively worse
bioavailability (49%) than oxadiazole 11a. This could be due to
the decreased measured aqueous solubility of compound 11b ver-
sus 11a. Of the amides 12a–c, each had comparable PK in the rat.
With all this information at hand, we now set out on our ultimate
goal to determine whether any of these compounds would be im-
proved inherently with regards to the atropisomerism issue.
CD spectroscopy is a useful tool for monitoring atropisomer
equilibration particularly for compounds which have chromoph-
ores. In order to achieve this, a timecourse CD spectrum of pure
MK-7725 and its respective enantiomer are subjected to a CD scan.
Once the basal levels of absorption are realized, a time course
experiment can be performed whereby MK-7725 is heated to
60 °C in EtOH over a 3 day period. The respective data obtained
at the 260 nm wavelength is plotted versus time in order to arrive
at a half-life calculation for the interconversion. In the case of MK-
7725, the t1/2 was calculated to 2.2 h. However, once we began to
examine novel derivatives such as 11a, 11b, and 12b an interesting
trend developed (Fig. 4). All three compounds possessed a half-life
greater than 250 h. This represented a major improvement and
makes subsequent development of these particular chemical enti-
ties significantly less complex and more cost-effective.
Atropisomer Interconversion as measured by CD
(60oC in EtOH)
% Initial CD Signal
100
80
MK-7725
11b
12b
60
40
11a
20
0
0
5
10
time (hours)
15
20
Figure 4. CD spectra for specific analogs of interest.
3. Conclusions
At this point, our goal was to introduce a bulky substituent alpha
to the oxadiazole ring present in MK-7725 (Fig. 2). With the desired
triflate 8 in hand, we sought to protect the free amine present. To
accomplish this, we chose phase transfer conditions using benzyl
bromide and benzyltriethylammonium chloride with 50% sodium
hydroxide in toluene. Upon heating to reflux, the desired benzyl
protected intermediate was isolated. Triflate 9 was subjected to a
modified palladium catalyzed coupling of trimethylsilylacetonitrile
using the S-Phos ligand.7,8 The resulting acetonitrile derivative 10
was treated with NaH followed by either MeI or diiodopropane giv-
ing rise to the respective gem-dimethyl nitrile (10a) or the cyclob-
utylnitrile (10b) derivative. Upon surveying a host of debenzylation
conditions, the most reproducible conditions were using TMS-I in
acetonitrile. The debenzylated acetonitrile derivative was con-
verted to the subsequent amide oxime, acylated with acetoxyisobu-
tyryl chloride, and cyclized thermally to furnish the desired 1,2,4-
oxadiazole. Compounds 11a and 11b were obtained in enantiopure
form after deacetylation with K2CO3/MeOH and subsequent chiral
HPLC resolution (Fig. 3).9,10
In summary, we were able to solve a long standing atropisom-
erism problem with the benzodiazepine sulfonamides. This in-
crease in the barrier of atropisomerism would allow for more
rapid development of a solid, stable crystalline form of these com-
pounds. In addition, any racemization at room temperature could
be avoided by building in a linker at the alpha position. The syn-
thetic complexity was increased but with the added benefit of a
>25-fold increase in the barrier of inversion. In addition, to our sur-
prise, these analogs generally maintained or improved upon exist-
ing potency values without a significant change in rat PK. Follow
up studies will be reported in due course.
References and notes
1. Chobanian, H. R.; Guo, Y.; Liu, P.; Chioda, M.; Lanza, T. J.; Chang, L.; Kelly, T. M.;
Kan, Y.; Palyha, O.; Guan, X.; Marsh, D. J.; Metzger, J. M.; Gorski, J. N.; Raustad,
K.; Wang, S.-P.; Strack, A. M.; Miller, R.; Pang, J.; Madeira, M.; Lyons, K.;
Dragovic, J.; Reitman, M. L.; Nargund, R. P.; Lin, L. S. ACS Med. Chem. Lett. 2012,
3. ASAP.
Primary and secondary amide derivatives were prepared via a
three-step sequence consisting of DIBAl-H reduction, Pinnick oxi-
dation,11 and EDC coupling. Enantiomerically pure compounds
12a, 12b, and 12c were then obtained by chiral HPLC resolution.
Compounds 11a and 11b both possessed excellent binding po-
tency (hIC50 = 1.4 and 0.6 nM) and both had very good mouse func-
tional activity (mEC50 = 67 and 76 nM) (Table 1). In comparison to
MK-7725, both compounds show a several fold improvement in
human binding potency in the in vitro assay. Simple amides such
as compounds 12b and 12c showed exquisite potency (hIC50 = 0.5
and 2.1 nM). In comparison to its truncated primary amide cousin,
compound 13, the intrinsic binding potency was improved by
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tance as a possible means to increase the barrier of inversion for
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