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D. M. Rotstein et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3116–3119
Table 3
Table 5
Pharmacokinetic profile in rata
Pharmacokinetic profile in rat and dog
Compd #
AUC PO (ngÁh/mL)
31
65
Cl IV (mL/min/kg)
%F
2.7
6.4
17
Pharmacokineticsa
24
215
99
15
28
4
19
21
134
151
131
Rat AUC (ng h/mL)
Rat Cl (ml min/kg)
Rat %F
108
105
18
309
Dog AUC (ng h/mL)
Dog Cl (ml min/kg)
Dog %F
4210
44
103
307
36
72
a
Doses were 1 mg/kg IV and 10 mg/kg PO, AUC and %F were determined after the
oral dose and Cl was determined from the IV dose.
a
IV/PO doses 1/10 mg/kg except for compound 28 in dog where IV/PO doses
be seen in Table 4, replacement of the cyclopentyl tail of 21, with
4,4-difluoro cyclohexyl or 3,3-difluorocyclobutyl afforded analogs
24 and 25, both of which showed improved antiviral activity, but
at a cost of microsomal stability. Substitution of a 3-fluoro or
3-chloro on the phenyl tail also increased antiviral potency (26–
29). However, the 3,5-difluorophenyl or 3-cyanophenyl analogs,
30–31, showed decreased antiviral activity.
As detailed in Table 5, screening of analogs 24 and 28 in rat PK
failed to show significant improvement in exposure. Interestingly,
when these compounds were administered to dogs, much im-
proved exposure was observed compared to rat despite similar
were 1/1 mg/kg. AUC and %F were determined after the oral dose and Cl was
determined from the IV dose.
paraformaldehyde gave 2,5-dibenzyltetrahydropyrrolo[3,4-c]pyr-
role-1,3-dione 34. Selective debenzylation with 1-chloroethyl
chloroformate, followed by imide reduction with lithium aluminum
hydride afforded 2-benzyloctahydro-pyrrolo[3,4-c]pyrrole 35.
((S)-3-Oxo-1-phenylpropyl)-carbamic acid tert-butyl ester 37
was prepared by BOC protection of (S)-3-amino-3-phenylpropionic
acid ethyl ester 36 using BOC anhydride, followed by chemoselec-
tive reduction of the ester to the corresponding aldehyde 37.
Reductive amination of amine 35 with aldehyde 37 using so-
dium triacetoxyborohydride gave intermediate 38. BOC removal
with HCl was followed by amide coupling with cyclopentanecarb-
oxylic acid, EDCI, HOBT and diisopropylethylamine to yield 39.
Debenzylation of 39 under catalytic hydrogenolysis conditions
afforded the respective amine, which was followed by amide for-
mation with 2,6-dimethylbenzoic acid to afford the desired prod-
uct, cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dimethylbenzoyl)
hexahydropyrrolo[3,4-c]pyrrol-2-yl]-1-phenylpropyl}amide, 4.
In summary, building from an in-house lead, an information-
based approach led to the rapid discovery of a series of novel
CCR5 antagonists with potent antiviral activity. Extensive SAR
studies afforded analogs with improved in vitro and in vivo DMPK
properties.
intrinsic microsomal stabilities (DLM clearance is 30 and 15 ll/
min/mg, respectively, for 24 and 28). One potential explanation
for this difference is the increased contribution of paracellular
absorption through the larger pore junctions in the dog gastro-
intestinal tract.
An example of the synthetic route utilized to prepare our series,
the synthesis of analog 4, is shown in Scheme 1.11
A [2,3]-dipolar cycloaddition between N-benzylmaleimide 32
and the imine ylide derived from N-benzylglycine 33 and
Table 4
Tail SAR of lead compound 21
R1
O
N
N
N
O
R2
R3
O
N Bz
O
N Bz
a
CO2H
R1
R2
R3
Binding
IC50
Antiviral
IC50
HLM/
RLM
Bz
N
Bz
N
+
#
a
a
O
32
O
33
34
H
b
21
24
25
26
27
28
29
30
31
H
14
27
20
13
12
9
27
6
35/51
83/46
60/61
129/17
113/24
28/29
N
N
N
N
N
N
N
N
N
N
N Bz
35
N
N
N
N
N
N
N
N
N
H
F
F
H
NH HCl
2
NHBoc
CHO
CO Et
c
2
F
37
H
3
36
F
NHBoc
e
d
H
N
35
37
+
3-Fl
3-Fl
3-Fl
3-Cl
3.6
1.1
0.8
2
38
N
N
Bz
H
F
F
f
O
N
F
O
N
H
H
F
N
N
O
N
H
F
F
Bz
H
182/
111
4
39
25
30
34
F
F
3,5-
Di-Fl
Scheme 1. Reagents and conditions: (a) (CH2O)n, toluene, reflux, 86%; (b) (i) 1-
chloroethyl chloroformate, CH2Cl2, reflux, 91%, (ii) LAH, THF, 70 °C, 95%; (c) (i)
NaOH, (BOC)2O, H2O, THF, (ii) DIBAL, CH2Cl2, À78 °C, 87%; (d) sodium triacetoxy-
borohydride, CH2Cl2, rt, 88%; (e) (i) HCl, MeOH, 50 °C, (ii) cyclopentanecarboxylic
acid, EDCI, HOBt, i-Pr2NEt, CH2Cl2, rt, 94% for two steps; (f) (i) ammonium
carbonate, Pd(OH)2, EtOH, reflux, (ii) 2,6-dimethylbenzenecarboxylic acid, EDCI,
HOBT, i-Pr2NEt, CH2Cl2, 56% for two steps.
41
203
45/ND
30/31
F
F
3-CN
a
Defined as in Tables 1 and 2.