1
476
A. G. Nair et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1475–1479
gt1 replicon activity, it possessed relatively weak activity against
other genotypes, and also had the potential to be an inducer of
CYP3A4 drug interactions (PXR EC50 = 3.3 lM). In order to improve
N
N
O
N
N
O
N
N
O
a
Cl
Si
Cl
O
O
upon MK-4882, our efforts focused upon the identification of alter-
nate structures which could effectively inhibit NS5A, be pan-geno-
typic, and alleviate any concern around potential metabolic
liabilities. Herein, we describe our efforts to investigate the impact
of introducing silyl proline variations into different HCV NS5A inhi-
bitors with the goal of identifying novel inhibitors that possess
both pan genotype activity and improved pharmacokinetic (PK)
properties over the corresponding carbon analogs.
O
Si
Si
1A
1B
Cl
C
Cl
1
1C'
b
O
Boc
O
Boc
N
N
HO
c
O
Incorporation of a silicon atom into drug molecules provides a
source of chemical diversity in drug design that has not been rou-
tinely explored, but has the potential to affect both biological and
pharmaceutical properties.12 Silicon has a larger covalent radius
than carbon, and also an increased C–Si bond length compared to
the corresponding C–C bond. The increased atom size and bond
length corresponds to a change in the size and shape of the silicon
analog relative to the corresponding carbon analog. These subtle
changes in size and shape can impact the way in which silicon ana-
logs interact with proteins. One essential part of HCV NS5A inhibi-
tors, such as MK-4882, is the S-Pro-S-Val dipeptide subunit. We
were intrigued by the idea that introduction of silicon into the pro-
line moiety might impact the replicon potency as well as the phar-
macokinetic properties of this class of inhibitors.
Si
Si
1E
1D
Scheme 2. Synthesis of silaproline analog 1E, Reagents and conditions: (a) n-BuLi,
78 °C; (b) 1. aq HCl, MeOH, rt; 2. DIPEA, NaI, CH Cl /Et O, rt; 3. Boc O, rt; (c) 1 M
aq KOH, MeOH, rt.
ꢀ
2
2
2
2
derivative 1E bearing the desired stereochemistry. It should be
noted that starting from -valine, an amino acid of the -series
[(S)-configuration] is obtained, but in the case of -silaproline 1E,
it corresponds to the (R)-configuration, due to changed atom
priorities.
The replicon genotype and 1aY93H mutant profile is tabulated
in Table 1. Compound 1, the dimethyl silyl proline analog of MK-
4882, demonstrated slightly weaker replicon activity on the geno-
types and mutants tested compared to the parent compound. Con-
sidering the physical and chemical diversity the dimethyl silyl
proline offers compared to the carbon analog, we felt this result
warranted further exploration on the impact that silyl proline
introduction might have with different analogs.
D
L
L
Silyl proline analogs described in this communication were con-
structed by methods similar to the carbon analogs published pre-
1
1
viously. Scheme 1 represents a general retrosynthetic approach
toward the silyl proline analogs starting from a Boc protected
silaproline fragment. This approach and other variations to accom-
modate different central cores have been described previously in
1
3
the patent literature.
The silyl proline monomer synthesis was achieved as according
to a known method starting from the Schollkopf chiral auxiliary
To further explore the effect of silyl prolines in conjunction with
different central cores, we synthesized analogs with the classical
biphenyl central core (Table 2). To our surprise, the one-sided silyl
proline analog 2a showed replicon activity comparable to the car-
bon analog 2 (daclatasvir). In addition, the 1aY93H mutant activity
of 2a was comparable to the carbon analog in our assay. It was also
noted that the symmetric analog 2b bearing silyl proline motifs on
both sides showed significantly weaker replicon potency across
several genotypes and the 1aY93H mutant.
1
4
shown in Scheme 2. Deprotonation of the bis-ether 1A, prepared
from the -Val-Gly diketopiperazine, with n-BuLi afforded a cyclic
D
anion intermediate which reacted with bis-(chloromethyl)
0
dimethylsilane 1B to afford compounds 1C and 1C . The diastere-
omers were separated by silica gel column chromatography
whereupon the desired compound, 1C, was subjected to HCl pro-
moted hydrolysis, DIPEA and NaI mediated ring closure, followed
by Boc-protection to afford Boc-silaproline analog 1D. Hydrolysis
of ester derivative 1D with 1 M KOH yielded the silyl proline
To further explore the impact symmetry may have on silyl
proline analogs, we investigated central core systems such as the
Val-Cap
Val-Cap
Central Core
O
O
O
N
O
N
H
N
O
Ar
Ar
N
N
H
N
H
N
O
N
H
Si
Proline
O
O
O
O
N
N
N
H
(HO) B/X
Ar
N
2
N
H
O
Ar
X/B(OH)
O
N
2
N
N
H
N
H
Si
O
Boc
O
O
N
HO
Br
N
O
N
H
N
H
Si
Si
Scheme 1. General synthetic approach to silyl proline analogs.