The direct, catalytic vicinal difluorination of terminal alkenes via an I(i)/I(iii) manifold was exploited to install a chiral, hybrid bioisostere of the CF3 and Et groups (BITE) in Gilenya®; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (log D) to be tempered compared to the corresponding CF3 and Et derivatives (CH2CH3 > CH2CF3 > CHFCH2F).
A stereodivergent
synthesis of four diastereomeric 2,3,4,5-tetrafluoropentanols
is disclosed. X-ray crystallographic analysis reveals conformations
that manifest sequential stereoelectronic gauche effects
(σC–H/C → σC–F*), thereby generating topological diversity via subtle C(sp3)–H to C(sp3)–F exchange. Two representative
tetrafluoro arrays have been incorporated into truncated analogues
of Gilenya for the management of relapsing remitting multiple sclerosis.
These closely similar multivicinal fluoroalkanes have notably different
physicochemical profiles and were found to be stable in the presence
of human microsomes.
A chiral,
hybrid bioisostere of the CF3 and Et groups
(BITE) was installed in a series of vorinostat (Zolinza) analogues,
and their histone deacetylase (HDAC) inhibitory behavior was studied
relative to that of their nonfluorinated counterparts. Several of
these compounds containing the 1,2-difluoroethylene unit showed in vitro potency greater than that of the clinically approved
drug itself against HDAC1. This trend was found to be general with
the BITE-modified HDAC inhibitors performing significantly better
than the ethyl derivatives. Installed by the direct, catalytic vicinal difluorination of terminal alkenes using an I(I)/I(III)
manifold, this underexplored chiral bioisostere shows potential in
drug discovery.
Matrix
metalloproteinases (MMPs) are involved in a spectrum of
physiological processes, rendering them attractive targets for small-molecule
drug discovery. Strategies to achieve selective inhibition continue
to be intensively pursued, facilitated by advances in structural biology.
Herein, we harness MMPs 2, 8, 9, and 13 to validate the vicinal difluoro motif as a hybrid bioisostere of CF3 and Et
(BITE) in a series of modified barbiturate inhibitors. Crystallographic
analyses of representative structures reveal conformations of the vicinal difluoro motif that manifest stabilizing hyperconjugative
interactions consistent with the stereoelectronic gauche effect. Detailed docking studies of a potent difluorinated probe
with MMP-9 are also disclosed and indicate that the structural basis
of inhibition is a consequence of the anisotropic nature of the motif.
Significant selectivity of MMP 13 versus MMP-2 can be achieved by
subtle chain contraction in a BITE-modified inhibitor.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.