C.J. Lim et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
An SAR investigation was conducted to assess the effects of sub-
stituents on the aryl moiety of 5-arylfuran-2-carboxamide derivatives 1
on UT binding affinities. Binding affinities of these substances to
membranes of HEK293 cells expressing the human UT receptor were
determined by using a competitive binding with Eu-labeled U-II and a
time-resolved fluorometric (TRF) assay.21 As can be seen by viewing the
data in Table 1, the unsubstituted 5-arylfuran-2-carboxamide derivative
1a has a moderate UT binding affinity (IC50 = 48 nM). Introduction of a
fluoro group at the meta-position (1c) leads to a 5.3-fold increase in the
UT binding affinity (IC50 = 9 nM). In contrast, substances having a
fluoro group at ortho- (1b) and para- (1d) positions display relatively
low UT binding affinities as reflected in their respective IC50 values of
93 and 68 nM. In addition, similar trends are observed for the chloro
(1e–g) and cyano (1h–j) substituted analogs with the meta-substituted
derivatives having the highest binding affinities (m-chloro (1f)
IC50 = 20 nM, m-nitrile (1i) IC50 = 40 nM). Other substances, including
those bearing m-nitro (1k), m-phenyl (1m) and m-methoxy (1o) sub-
stituted aryl groups, have higher UT binding affinities than their re-
spective para-substituted counterparts 1l, 1n, and 1p. Interestingly, 5-
arylfuran-2-carboxamide derivatives containing ortho-alkyl and -alkoxy
groups (1q–1u) have high UT binding affinities with IC50 values falling
between 14 and 18 nM.
Fig. 1. Representative UT antagonists.
Fig. 2. 5-Arylfuran-2-carboxamide derivatives.
arylfuran-2-carboxamide derivatives 1 is outlined in Scheme 1. The
bromofuran-2-carboxylate with a variety of aryl boronic acids using
Suzuki coupling conditions to form the corresponding methyl 5-aryl-
substituted furan-2-carboxylates 2. Hydrolysis of the esters 2 using 3 M
NaOH in MeOH formed the respective carboxylic acids 3 in high yields.
In a parallel sequence employed to synthesize the coupling partner for
introduction of the piperazine moiety in the targets, 3-chloro-4-hy-
droxybenzaldehyde 5 was reacted with tert-butyl 4-((methylsulfonyl)
oxy)piperidine-1-carboxylate in the presence of potassium carbonate to
generate tert-butyl 4-(2-chloro-4-formylphenoxy)piperidine-1-carbox-
aldehyde 6. Reductive amination of 6 with piperazine using sodium
triacetoxyborohydride in tetrahydrofuran produced 1-(3-chloro-4-(pi-
peridin-4-yloxy)benzyl)piperazine 7. Carboxylic acids 3 were converted
to the corresponding chlorides in situ using thionyl chloride, which then
underwent amide coupling reactions with the piperazine derivative 7 in
the presence of triethylamine to produce amides 4. Subsequent removal
of the N-Boc groups in 4 by treatment with conc. HCl in 1,4-dioxane
generated the targets 1.
The effects on UT binding of multiple aryl ring substituents on the 5-
aryl group of the furan-2-carboxamides were also assessed. The results
show that the 3,4-dimethoxy (1aa) and 3,4-dichloro (1ab) aryl deri-
vatives have UT binding affinities that are close to that of the parent 1a.
Likewise, analogs bearing 2,3- (1v), 2,4- (1w), 2,5- (1x) and 3,5- (1z)
difluoro phenyl groups, and one containing a 3,4,5-trifluorophneyl
group (1ac) display binding affinities in the range of IC50 value between
15 and 61 nM. In stark contrast, the 3,4-difluoro analog 1y was found to
exhibit the most potent UT binding affinity (IC50 = 6 nM) among all of
Furthermore, antagonistic activities of 5-arylfuran-2-carboxamide
derivatives 1 were also evaluated by measuring the change of U-II-in-
duced intracellular calcium concentration in HEK293-aeq/UT cells.23
As shown in Table 1, all of the derivatives showed a typical con-
470 nM except for 1n. Among those tested, 1e has the most potent
inhibition with IC50 value of 50 nM. In addition, 1y also exhibited
Scheme 1. Reagents and conditions: (a) ArB(OH)2, Pd(PPh3)4, 3 N Na2CO3, 1,4-dioxane, 100 °C, 5 h; (b) 3 N NaOH, MeOH, rt, 30 min.; (c) (i) SOCl2, 1,2-di-
chloroethane, 120 °C, 2 h. (ii) 7, Et3N, dichloromethane, rt, 30 min.; (d) 4 M HCl, 1,4-dioxane, rt, 2 h.; (e) K2CO3, DMF, 80 °C, 19 h.; (f) (i) piperazine, Na2SO4, THF, rt;
(ii) NaBH(OAc)3, THF, 60 °C, 1 h.
2