5092
K. M. Boy et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5089–5093
Table 2. Percent relaxation of phenylephrine-contracted rabbit corpus
cavernosum tissue strips (drug concentration 10 lM)9,10
least of all by the necessity of high-purity crystalline
salts for successful reaction. A solution in the form of
a b-methoxy ketone provided a common intermediate
for high-throughput synthesis of b-amino ketones. In
the event, reaction of 29 with 1-bromo-4-methoxy-
butan-2-one under basic conditions provided intermedi-
ate 31, which upon exposure to the desired amine and
K2CO3 in ethanol underwent a retro-Michael elimina-
tion/Michael addition to provide the desired amines.
The c-amino ketones 13 and 14 were obtained in
straightforward fashion by reaction of 29 with 5-bro-
mo-1-chloro-pentan-2-one, followed by amine displace-
ment in THF. The amino alcohols 15 and 16 were
prepared directly from thiol 29 by adding the thiol to
pre-mixed epichlorohydrin and the desired amine. While
exposure of ketones 11–14 to NaBH4 produced over-
reduced products, the action of NaBH3CN cleanly
produced the analogous alcohol products 17–20.
Compounds
Percent relaxation of tissue strips (%)
1a
2a
21
32
35
28
34a
19
19a
45a
17a
16
35
22
30
23a
37a
29
36
28a
37
14
35
22
17
67
19
30
57
49
48
44
2f
4a
4b
4c
4d
4e
4f
4g
6a
6b
6c
6d
6e
6f
8a
8b
8c
3. Results and discussion
10a
10b
10c
10d
10e
10f
12a
16a
16c
16d
16e
Initial investigation by voltage-clamp techniques8 in hu-
man Maxi-K cRNA microinjected oocytes of the com-
pounds synthesized revealed many general trends in
the SAR. First, the series of phenols were universally
more active than the corresponding methyl ethers (Table
1, compare 1 vs 2 and 15 vs 16). Secondly, robust levels
of activity were maintained in compounds of structure II
(4, 6, 8), even though the length of the spacer varied
from 1 to 3 carbons. A similar consistency of activity
was observed within compounds of type III (10, 12,
14). Additionally, this insensitivity to tether length was
conserved even when chemotypes II and III are com-
pared. Compounds II and III differ by replacing the phe-
nyl group and adjoining NH moiety in series II with a
single methylene group. The difference in S–C(O) dis-
tance as well as the difference in the electronics of ke-
tones 11–14 and amides 3–8 had little effect on
activity. The side chain also influenced the activity of
the quinolinones. Simple aminoalkyl S-3 quinolinones,
for example, were devoid of activity (data not shown).
Similar to the ketones and amides of type III, the alco-
hols of type IV (16, 18, 20) were active regardless of
spacer length. Good to excellent activity was observed
for these alcohols, the additional possible H-bond
donating property was not detrimental to their utility.
a n = 2.
channels. Of the compounds, which were active in the
tissue strip assay, the aniline-based amides 4e, 6e, and
8c demonstrated modest levels of activity. These com-
pounds have a diamine structure in common. The activ-
ity of ketones 12 and 14 did not translate well into the
strips, but amides 10a–f did provide tissue relaxing
properties, with the isonipecotamide based amide 10e
having exemplary activity. Amino alcohols 16a–e pro-
vided a rich class of active maxi-K openers with tissue
relaxing activity. Simple amines (diethylamine, morpho-
line, thiomorpholine) as well as derivatized piperazines
were all robustly active. The confluence of a H-bond
acceptor and a remote amino group on the side chain
of these compounds is a consistent feature among the
most potent maxi-K openers presented in this paper,
and is hypothesized to be responsible for the activity
observed.
Several amines potently opened maxi-K channels when
incorporated into the molecules. Among them, N-
methyl piperazine and other diamines such as N,N0,N0-
trimethylethylenediamine and 4-piperidinylpiperidine
were the best. Morpholine and pyrrolidine also often
exemplified robust levels of activity.
3-Thio-quinolinones provide a platform on which is
built potent openers of the maxi-K channel in vitro as
well as in tissue preparations. The in vivo characteriza-
tion of these compounds will be disclosed in due course.
Evaluation of pertinent compounds in a secondary assay
was accomplished by noting the degree of relaxation of
pre-constricted strips of rabbit corpus cavernosum. In
many cases (Table 2), potent channel opening did not
translate into tissue relaxation in the preparations. This
may be due to tissue-penetration issues for some com-
pounds, or may be due to a difference in the channels
expressed in the oocytes versus the naturally occurring
References and notes
1. Gribkoff, V. K.; Starrett, J. E., Jr.; Dworetzky, S. I.
Neuroscientist 2001, 7, 166–177.
2. Korovkina, V. P.; England, S. K. Clin. Exp. Pharmacol.
Physiol. 2002, 29, 317–323.
Boy, Kenneth M.
