W. Nguyen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7106–7109
7109
From a structural perspective we saw partial similarities to the
known Kv1.3 blockers UK 78,282, verapamil and PAP-1 (Fig. 1).
These included the basic aliphatic nitrogen, diphenylmethyl moi-
ety, cyano group and the location of aromatic rings at both ends
of the molecules. We began by pruning these functional groups
on diphenoxylate to explore their effect on Kv1.3 blockade. In some
cases these groups were replaced by other functional groups of
varying sizes and properties.
The principle outcomes were the demonstration that Kv1.3
blockade could be maintained and even enhanced by the removal
of one or more of diphenoxylate’s key functional groups. For exam-
ple, removal of the R4-phenyl ring and the nitrile was tolerated
activity at opioid receptors. The ester on diphenoxylate is metabo-
lised in vivo to the carboxylic acid (diphenoxin) which is the active
opioid agent.22 Any future work would need to monitor mu opioid
activity and avoiding an ester would need to be considered. Com-
pound 14 circumvents this problem, however any optimization of
9 would need to bear this in mind.
This study has identified two new series of Kv1.3 blockers de-
rived from the anti-diarrhoeal compound diphenoxylate. Succes-
sive deletion of functional groups was able to improve activity
although the SAR was not consistent between the compound clas-
ses. Removal of the ester, cyano and an aromatic ring were toler-
ated and in many cases improved activity. These deletions also
reduced both MW and lipophilicity presenting compounds worthy
of further investigation. There is a need for Kv1.3 blockers with
improved selectivity and biopharmaceutical properties, and this
study provides a starting point for further investigations.
such that compound 9 (IC50 0.8 lM) had improved potency. The
replacement of the phenyl and carboxylic ester substituents by a
single hydroxyl group in compound 14 also showed improved
activity (IC50 0.75
lM). The combination of these modifications
however, yielded a poorly active compound 17 (IC50 > 100
lM).
This contradicted the overall pharmacophore that we had tenta-
tively proposed12 for Kv1.3 inhibitors. The inner cavity, which con-
stitutes the binding site for most small molecule Kv1.3 blockers is
somewhat large19 and it seems probable that the compounds bind
in various ways such that a single pharmacophore will not describe
the SAR.
Acknowledgments
The authors would like to thank Roger Riordan and the Cybec
Foundation for their financial support towards this research.
Supplementary data
From a drug discovery perspective, the retention of blockade
with both reduced molecular size and lipophilicity is encouraging.
While PAP-1 shows good potency it has no ionizable functional
groups and a logP value of 4.0314 resulting in a relatively low oral
availability of only 25% and solubility issues for formulation.20 Both
compounds 14 and 9 have reduced ClogD7.4 values relative to
diphenoxylate as well as reduced molecular weights (320.4 and
351.5, respectively). Diphenoxylate is a poorly soluble substance
due to its relatively high lipophilicity (ClogD7.4 4.27). The lipophil-
icity of compound 9 was reduced (ClogD7.4 3.47) however, the re-
Supplementary data associated with this article can be found, in
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Another important aspect of investigating the SAR of diphen-
oxylate is to place focus on the ester group which is linked to its