Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin- 1-yl-acetic acid antagonists of the human CCR5 chemokine receptor

Article abstract of DOI:10.1016/j.bmcl.2004.04.078

Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.

Full text of DOI:10.1016/j.bmcl.2004.04.078

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3419–3424
Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-
pyrrolidin-1-yl-acetic acid antagonists of the human CCR5
chemokine receptor
K. Shankaran,a,* Karla L. Donnelly,a Shrenik K. Shah,a Ravindra N. Guthikonda,a
Malcolm MacCoss,a Sander G. Mills,a Sandra L. Gould,b Lorraine Malkowitz,b
Salvatore J. Siciliano,b Martin S. Springer,b Anthony Carella,c
Gwen Carver,c Daria Hazuda,c Karen Holmes,c Joseph Kessler,c
Janet Lineberger,c Michael D. Miller,c Emilio A. Eminic and William A. Schleifc
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Immunology Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA
Received 13 February 2004; revised 20 April 2004; accepted 26 April 2004
Available online
Abstract—Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems
from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The syn-
thesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a
HeLa cell-based HIV-1 infectivity assay are discussed.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
no expression of this receptor on their cell surfaces and
are thus highly resistant to HIV-1 infection.4;5 These
observations provided compelling evidence that a suit-
able small molecule CCR5 receptor antagonist might
have potential in the treatment of HIV-1 infection and/
or prevention.
During the past two decades the global HIV/AIDS
epidemic has had a devastating impact both in social
and economic terms. The current multiple drug-cocktail
therapies have stabilized AIDS in the US, but a resur-
gence is being experienced today due to increasing
incidences of drug resistant viruses. Thus, there is gen-
uine need to explore newer strategies to confront HIV-1
infection and proliferation.
Rapid strides made during the past few years toward the
development of CCR5 receptor antagonists have
resulted in several publications from many laborato-
ries.6;7 A recent communication from this laboratory
showed that compounds incorporating a 1,3,4-trisub-
stituted pyrrolidine ring scaffold (1) were potent CCR5
antagonists.8a During further development of this lead
class we sought a more selective agent by restricting the
free movement of the propyl side chain in 1a by incor-
poration of several heterocyclic spacers. It was hoped
that such a modification (2) might provide agents with
better antiviral and pharmacokinetic properties. Evi-
dence of the beneficial aspects of a heterocyclic spacer
was seen the case of pyrazoles (1b) as recently
reported.8b–d
Earlier work had identified the two chemokine recep-
tors, CCR5 and CXCR4, as co-receptors along with
CD4 for the entry of macrophage-tropic and T-cell
tropic strains of HIV-1, respectively.1–3 It was subse-
quently discovered that certain individuals homozygous
for a 32-base pair deletion in the gene for CCR5 show
* Corresponding author. Tel.: +1-732-5943979; fax: +1-732-5943007;
e-mail: kothandaraman_shankaran@merck.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.078

3420
K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3419–3424
Table 1. CCR5 binding/antiviral activity of heterocycle modified
pyrrolidineacetic acid analogs14
R1
N
N
N
N
R
N
N
R
N
1a
1b
R2
COOH
COOH
N
1
COOH
O
R1
N
R1
NH
+
R
Entry
Binding IC50 (nM) HeLa IC90 (nM)
N
N
3
2
R2
R2
R1 = hereroaryl, R2 = alkyl
O
COOPMB
COOH
N
4
30
18.1
27
ND
ND
Ph
N
O
31
Ph
H
N
2. Chemistry
32
33
34
35
23
ND
33
N
The strategy for the synthesis of derivatives related to 2
involved the reductive amination of novel 4-heterocyclic
piperidines 3 with the requisite pyrrolidine aldehydes 4
in the key step as previously reported for 1.8 The syn-
theses of several piperidine analogs 3 bearing a variety
of heterocyclic rings at C-4 are briefly discussed below.
Ph
N
6.2
1.1
N
N
N
Ph
H
H
S
100
ND
Ph
The preparation of the isomeric 3- and 5-phenyl-1,2-
oxazole derivatives 6 and 7 (entries 30 and 31, Table 1)
was straightforward by literature methods.9 The 1,3-
dipolar addition of the respective nitrile oxide (derived
from oxime 5) and the requisite acetylene as shown in
Scheme 1 gave either 6 or 7 after deprotection of the
N-Boc with HCl in methanol.
N
0.67
Bn
S
36
37
38
39
1.3
2.0
0.29
1.5
33
N
Bn
N
33
S
Bn
Scheme 2 details the preparation of the 4-phenyl imid-
azole 11 (entry 32, Table 1) by a literature method,10
which involved lithiation of 8 followed by reaction with
N-Boc piperidone to afford 9. Dehydration of 9 followed
by catalytic hydrogenation resulted in 10. Removal of
the protecting groups on 10 using standard protocols
then afforded 11.
N
0.14
100
S
Bn
N
O
Bn
ND ¼ Not determined.
The synthesis of the isomeric 2-phenyl imidazole 14 is
shown in Scheme 3 (entry 33, Table 1). A three-step
sequence starting from acid 12a, which involved for-
mation of the acid chloride, reaction with diazomethane,
and then decomposition of the intermediate diazoketone
with hydrogen bromide (gas) afforded a-bromoketone
13. Reaction of 13 with benzamidine, followed by
saponification of the benzoyl, afforded 14.
O
b, c
a
R2
N
R1-CHO
R1-CH=NOH
5
R1
R1 = Ph , R2 =
R1 = Ph or
R2 =
NBoc
6
7
NH
NH , R2 = Ph
NBoc or Ph
R1 =
Scheme 1. Reagents and conditions: (a) NH2OHÆHCl, Py, rt; (b)
(n-Bu3Sn)2O, t-BuOCl, and R2CCH; (c) HCl, MeOH.
Interestingly, an analogous reaction of 13 with phenyl-
acetamidine followed by saponification failed to yield
the homologous 2-benzyl imidazole product. Alterna-
tively, the imidazole 17 (entry 35, Table 1) was synthe-
sized (Scheme 4) via the N-Boc protected a-bromo
compound 15. We anticipated that the N-Boc in 15
would allow for easier N-deprotection in the final step.
The three-step procedure from acid 12b (as the N-Boc)
involving Weinreb amide formation, addition of methyl
Grignard, and a-bromination yielded 15. Reaction of 15
with commercially available 2,6-diclorophenylacetam-
idine gave benzyl 16 after transfer hydrogenation to
remove the chloro substituents. Finally, the N-Boc
removal, now under standard acidic conditions, afforded
the desired 17.
The N-Boc imidazole 16 was further functionalized
(Scheme 5) to yield 18 and 20, which were necessary to
complete the SAR within this imidazole class (entries 49
and 50, Table 3) Thus, 16 underwent electrophilic sub-
stitution with either NCS or iodine to furnish 18 (after
N-Boc removal) or 19. The iodo compound 19 under-

K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3419–3424
3421
H
N
OTMS
OTMS
NBoc
OTMS
NBoc
d, e
N
a
b, c
N
N
NH
N
N
NHO
N
Ph
Ph
Ph
Ph
11
8
10
9
Scheme 2. Reagents and conditions: (a) n-BuLi/THF, then N-Boc-piperidone; (b) MsCl, DIPEA, CH2Cl2; (c) PtO2/EtOH, H2; (d) TBAF, THF; (e)
HCl, MeOH.
a, b, c
d, e
tropropane to furnish aminols 22 after catalytic reduc-
tion. The aminols 22 were then acylated and oxidized to
afford 23. The ketoamides 23 underwent smooth cyc-
lodehydration with Lawesson’s reagent to furnish 24
and 25 after the usual Boc deprotection.
O
O
NBz
N
NH
NBz
Br
HO
NH
14
Ph
12a
13
Scheme 3. Reagents and conditions: (a) SOCl2; (b) CH2N2/ether;
(c) HBr (gas); (d) benzamidine, CHCl3, reflux; (e) KOH, MeOH.
General approaches to the preparation of the 2-benzyl-
1,3-oxazoles 28 and 29 (entries 39, Table 1, and 51,
Table 3) are shown in Scheme 7.12 Addition of vinyl
magnesium bromide to aldehyde 21 followed by reaction
with phenylacetic acid under DCC/DMAP conditions
provided the ester 26. Ozonolysis of 26 followed by a
reductive workup gave the intermediate aldehyde or
ketone, which on refluxing with ammonium acetate
afforded the oxazoles 27. Removal of the N-Boc pro-
tection of 27 then gave desired products 28 and 29.
went a three-step sequence that involved vinylation,
catalytic reduction, followed by deprotection to furnish
20.
The preparation of the 1,3-thiazoles (entries 34 and 36,
Table 1) was accomplished by literature methods11
starting from the appropriate a-bromoketone and thio-
amide as was accomplished in Scheme 4. The isomeric
thiazole analog 24 (entry 37, Table 1) and its 4-ethyl
analog 25 (entry 52, Table 3) were prepared (Scheme 6)
by nitroaldol reaction of 21 with nitromethane or 1-ni-
The synthesized heterocyclic compounds discussed
above were reductively aminated with 4 and in one or
f
d, e
Ph
O
a, b, c
O
N
N-H
N-Boc
12b
N
N-Boc
N-Boc
HO
NH
Br
NH
Ph
15
16
17
Scheme 4. Reagents and conditions: (a) DCC, DMAP, NHMeOMe; (b) MeMgI/ether; (c) LDA/TMSCl, then NBS; (d) 2,6-dichloro-phenylace-
amidine, CHCl3, reflux; (e) Pd/C, ammonium formate, AcOH/water; (f) EtOAc/HCl.
Cl
I
c, d, e
a, e
b
N
NH
N
NH
N
NBoc
16
NH
NH
NH
19
Ph
Ph
Ph
20
18
Scheme 5. Reagents and conditions: (a) NCS, CHCl3, reflux; (b) I2/NaOH, THF; (c) vinyltin, Pd(PPh3)4, DMF, 110 °C; (d) Pd/C, H2, MeOH; (e)
EtOAc/HCl.
R
R
O
NH2
e, f
Ph
a, b
c, d
R
N
NH
HN
NBoc
NBoc
NBoc
S
O
O
HO
Ph
23
21
22
24, R = H
25, R = Et
Scheme 6. Reagents and conditions: (a) RCH2NO2, DBU THF; (b) Pd/C, MeOH, H2; (c) PhCH2COOH, DCC/DMAP, CH2Cl2; (d) chromic acid/
ether; (e) Lawesson’s reagent; (f) EtOAc/HCl.
R
R
R
a, b
c, d
e
N
N-H
N
N-Boc
21
N-Boc
O
O
O
O
Ph
Ph
28, R = H
29, R = Et
Ph
27
26
Scheme 7. Reagents and conditions: (a) vinyl grignard, THF; (b) phenylacetic acid, DCC/DMAP, THF; (c) O3, MeOH/CH2Cl2, )78 °C, then PPh3,
rt; (d) ammonium acetate, AcOH, reflux; (e) EtOAc/HCl.

3422
K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3419–3424
Table 2. CCR5 binding activity of alkyl substituted pyrrolidineacetic
acid analogs14
HeLa Magi cells that expressed both CXCR4 and CCR5
receptors and the results are expressed with the more
stringent IC90’s (nM).14;15 The SAR for these analogs
was initially centered on the modification of the het-
erocyclic moiety at C-4 of the piperidine and selected
alkyl substituents at the acetic acid appendage on the
pyrrole nitrogen. The results of these two modifications
were then later incorporated to generate hybrid analogs
that also incorporated additional substituents at the
heterocyclic ring. Accordingly, initial results from the
placement of various heterocycles on the piperidine ring
at C-4 are shown in Table 1. Notice that all the com-
pounds displayed in Table 1 had the cyclohexylacetic
acid substituent at the pyrrolidine nitrogen.
R
N
N
R1
COOH
R
R1
Entry
Binding IC50 HeLa IC50
(nm)
(nM)
i-Pr
40
41
42
7.0
300
N
0.73
0.38
100
100
N
O
Ph
Ph
H
i-Pr
i-Pr
43
44
45
3.8
300
3.7
3.7
Relative comparison of the binding potency among the
first 4 entries (30–33) in Table 1 clearly indicates that the
2-phenylimidazole analog (33) was 3–4-fold more potent
than the other analogs. The imidazole 33 also exhibited
N
1.6
0.34
46
47
48
0.51
0.23
0.23
11
a
modest activity in the HeLa antiviral assay
(IC90 ¼ 33 nM). The surprising result was the 2-phenyl-
1,3-thiazole (34), which showed binding affinity that was
significantly better than 33, however, it was 3-fold less
potent in HeLa antiviral assay. Both oxazole isomers 30
and 31, as well as the isomeric 4-phenylimidazole analog
32 were comparatively less potent. The impressive
binding potencies observed for 33 and 34 led us to ex-
plore these derivatives further with the preparation of
the benzyl analogs 35–36, the isomeric benzyl thiazoles
37–38, and 1,3-oxazole 39. These benzylic analogs uni-
formly displayed superior binding affinity with the
imidazole 35 and thiazole 38 now displaying binding
affinities in the sub-nanomolar range. Relative com-
parison of the thiazole analogs 34 and 36 indicated that
going from the phenyl to benzyl did not make much
difference in the binding affinity, but the antiviral
activity for 36 was 3-fold better. The beneficial effect on
the binding affinity of the benzyl replacement for phenyl
appeared to also be borne out by the other isomeric
thiazole analogs 37 and 38 and the 5-benzyl-1,3-oxazole
39.
N
0.13
0.13
S
Ph
Table 3. CCR5 binding activity of cyclobutylmethyl substituted
pyrrolidineacetic acid analogs14
R
N
F
N
COOH
R
Entry
Binding IC50 (nM) HeLa IC50 (nM)
N
N
49
0.57
0.60
0.4
N
Ph
Ph
H
Cl
50
0.13
N
H
It is interesting to observe from Table 1 that high
binding affinity was not sufficient for good antiviral
activity, or at least not until sub-nanomolar binding was
achieved as with 38. This suggests that additional factors
such as protein binding, cell wall penetration or other
mechanisms may also be involved. The observation was
also made that a nitrogen lone pair at the 3 position
relative to the piperidine linkage, as well as the benzylic
substitution at the 4 position, was critical for both
binding and antiviral activities.8b In light of these
observations and the impressive CCR5 binding and
HeLa antiviral activity of 38, we were encouraged to
further optimize the antiviral activity based on the
pyrrolidineacetic acid substitution. These efforts led to
the preparation of analogs in the 2-benzylimidazole, 2-
benzyl-1,3-oxazol-5-yl, and 2-benzylthiazol-5-yl series as
shown in Table 2.
N
N
51
52
0.89
0.76
0.13
0.13
O
S
Ph
Ph
more subsequent steps8 (i.e., deprotection of pyrroli-
dineacetic acid) afforded the products listed in Tables 1–
3, the SAR of which are discussed below.
3. Results and discussion
The synthesized compounds were routinely screened for
both CCR5 binding affinity and inhibition of viral
infectivity (HeLa assay) and the results are summarized
in Tables 1–3. The CCR5 receptor binding assay utilized
125I-MIP-1a as the ligand and the results are given as
IC50’s (nM).12;13 The HIV-1 infectivity assay utilized
Modification at the acetic acid end for each heterocycle
involved the incorporation of three specific substituents:
namely, the iso-propyl, cyclopropylmethyl, and cyclo-

K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3419–3424
3423
Binding IC50 (nM) HeLa IC50 (nM) Clp (mL/min/kg) Vdss (L/kg) t1=2 (h) % F
Cl
N
N
N
N
F
F
NH
0.7
1.0
0.4
60.5
1.05
0.54
0.53
0.84
1.1
Ph
Ph
N
N
53
COOH
COOH
S
0.13
10.15
19
54
butylmethyl groups, respectively. The results for these
analogs (40–48, Table 2) were compared with the anal-
ogous heterocyclic compounds in the cyclohexyl series
(Table 1).8a In the imidazole series, while the iso-propyl
analog 40 lost potency in both the binding and antiviral
assays, the cyclopropylmethyl 41 and cyclobutylmethyl
42 by and large retained the binding potency of 35 and
showed moderate antiviral activity in the HeLa assay.
The iso-propyl oxazole analog 43 mimicked the imid-
azole 40 with respect to loss of binding potency. How-
ever, the analogs 44 and 45 displayed both good affinity
and an impressive 25-fold gain in the anti-HIV activity.
The gain in the antiviral potency for the corresponding
thiazole analogs 47 and 48 was even more dramatic by
two orders of magnitude. Interestingly, even the iso-
propyl 46 showed desirable activity. This result would
prove important for PK reasons as discussed below.
Thus, it appeared from Table 2 that the presence of the
smaller alkyl groups of these analogs lead to significant
enhancement in antiviral activity with little or no com-
promise in the binding activity. These results were then
incorporated into additional analogs wherein the het-
erocyclic ring was further derivatized with a chloro or
ethyl as shown in Table 3.8b We also replaced the un-
substituted phenyl group on the pyrrolidine ring with a
3-fluorophenyl, which had been demonstrated to en-
hance the metabolic stability for this pyrrolidine scaf-
fold.8a;b
antagonists in the literature. The rat pharmacokinetics
studies (IV and PO) indicated that the imidazole 53 still
suffered from a high clearance and short half-life.
However, 54 appeared better as characterized by its
lower clearance and good oral bioavailability.
In conclusion, in lieu of the 3-phenylpropyl-side chain of
1a, a variety of heterocyclic scaffolds, in addition to the
pyrazole of 1b, were found to afford very potent com-
pounds in both CCR5 binding and in a HIV-1 HeLa
cell-based infectivity assay. Furthermore, we have con-
firmed that with the placement of appropriate substitu-
ents on the heterocycle and with the proper choice of
alkyl substitution at the acetic acid side chain increased
antiviral potency and improved pharmacokinetics can
be achieved.
Acknowledgements
Drs. Paul Finke and Tim Waddell are thanked for
helpful suggestions and discussions.
References and notes
1. Reviews: (a) Garzino-Demo, A.; Devico, A. L.; Gallo, R.
C. J. Clin. Immunol. 1998, 18, 243; (b) Hunt, S. W., III;
LaRosa, G. J. Ann. Rep. Med. Chem. 1998, 33, 263; (c)
Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4,
80; (d) Schwartz, M. K.; Wells, T. N. C. Exp. Opin. Ther.
Patents 1999, 9, 1471.
A comparison of the imidazole analogs 49 and 50 with
42 (Table 2) indicates that both the ethyl and chloro
substituents had remarkable effects (several fold!) in
enhancing the antiviral properties that we had not seen
previously for these compounds. The oxazole compound
45 also benefited by the placement of an ethyl sub-
stituent as in 51. However, the presence of ethyl group
on the thiazole compound 52 was not able to further
enhance the antiviral properties of 47 and 48. Subse-
quently, we realized that these substituted heterocycles
in combination with an iso-propyl or cyclopropylmethyl
moiety would suffice to generate potent analogs with
improved PK properties. Shown above are two addi-
tional compounds, 53 and 54, that were subsequently
evaluated for their PK profiles in the rat.
2. Cocchi, F.; DeVico, A. L.; Garzino-Demo, A.; Arya, S.
K.; Gallo, R. C.; Lusso, P. Science 1995, 270, 1811.
3. (a) Feng, Y.; Broder, C. C.; Kennedy, P. E.; Berger, E. A.
Science 1996, 272, 872; (b) Choe, H.; Farzan, M.; Sun, Y.;
Sullivan, N.; Rollins, B.; Ponath, P. D.; Wu, L.; Mackay,
C. R.; LaRosa, G.; Newman, W.; Gerard, N.; Gerard, C.;
Sodroski, J. Cell 1996, 85, 1135; (c) Doranz, B. J.; Rucker,
J.; Yi, Y. J.; Smyth, R. J.; Samson, M.; Peiper, S. C.;
Parmentier, M.; Collman, R. G.; Doms, R. W. Cell 1996,
85, 1149; (d) Deng, H.; Liu, R.; Ellmeier, W.; Choe, S.;
Unutmaz, D.; Burkhart, M.; DiMarzio, P.; Marmon, S.;
Sutton, R. E.; Hill, C. M.; Davis, C. B.; Peiper, S. C.;
Schall, T. J.; Littman, D. R.; Landau, N. R. Nature 1996,
381, 661; (e) Dragic, T.; Litwin, V.; Allaway, G. P.;
Martin, S. R.; Huang, Y.; Nagashima, K. A.; Cayanan,
C.; Maddon, P. J.; Koup, R. A.; Moore, J. P.; Paxton, W.
Both 53 and 54 had comparable potency and are per-
haps much more potent than other leading CCR5

3424
K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3419–3424
A. Nature 1996, 381, 667; (f) Alkhatib, G.; Combardiere,
C.; Broder, C. C.; Feng, Y.; Kennedy, P. E.; Murphy, P.
K.; Meurer, L. C.; Oates, B.; Mills, S. G.; MacCoss, M.;
Malkowitz, L.; Springer, M. S.; Carella, A.; Carver, G.;
Holmes, K.; Emini, E. A.; Schleif, W. A. National
Meeting of American Chemical Society, Washington,
DC, 2000, MEDI-120; (i) Palani, A.; Shapiro, S.; Clader,
J. W.; Greenlee, W. J.; Vice, S.; McCombie, S.; Cox, K.;
Strizki, J.; Baroudy, B. M. Bioorg. Med. Chem. Lett. 2003,
13, 709, and other references cited therein.
M.; Berger, E. A. Science 1996, 272, 1955.
4. (a) Samson, M.; Libert, F.; Doranz, B. J.; Rucker, J.;
Liesnard, C.; Farber, C. M.; Saragosti, S.; Lapoumeroulie,
C.; Cognaux, J.; Forceille, C.; Muyldermans, G.;
Verhofstede, C.; Burtonboy, G.; Georges, M.; Imai, T.;
Rana, S.; Yi, Y.; Smyth, R. J.; Collman, R. G.; Doms,
R. W.; Vassart, G.; Parmentier, M. Nature 1996, 382, 722;
(b) Liu, R.; Paxton, W. A.; Choe, S.; Ceradini, D.; Martin,
S. R.; Horuk, R.; MacDonald, M. E.; Stuhlmann, H.;
Koup, R. A.; Landau, N. R. Cell 1996, 86, 367.
5. Michael, N.; Chang, G.; Louie, L. G.; Mascola, J. R.;
Dondero, D.; Birx, D. L.; Sheppard, H. W. Nature Med.
1997, 3, 338.
6. For a comprehensive review on this subject, see: Kaz-
mierski, W.; Bifulco, N.; Yang, H. B.; Boone, L.; DeAnda,
F.; Watson, C.; Kenaki, T. Bioorg. Med. Chem. 2003, 13,
2663.
8. (a) Lynch, C. L.; Hale, J. J.; Budhu, R. J.; Gentry, A. L.;
Mills, S. G.; Chapman, K. T.; MacCoss, M.; Malkowitz,
L.; Springer, M. S.; Gould, S. L.; DeMartino, J. A.;
Siciliano, S. J.; Cascieri, M. A.; Carella, A.; Carver, G.;
Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2002, 12, 3001; (b) Shen, D.-M.;
Shu, M.; Mills, S. G.; Chapman, K. T.; Malkowitz, L.;
Springer, M. S.; Gould, S. L.; DeMartino, J. A.; Siciliano,
S. J.; Cascieri, M. A.; Carella, A.; Carver, G.; Holmes, K.;
Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.;
Miller, M.; Schleif, W. A.; Emini, E. A. Bioorg. Med.
Chem. Lett. 2004, 14, 935; (c) Shen, D.-M.; Shu, M.;
Willoughby, C. A.; Shah, S. K.; Lynch, C. L.; Hale, J. J.;
Mills, S. G.; Chapman, K. T.; Malkowitz, L.; Springer, M.
S.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.;
Cascieri, M. A.; Carella, A.; Carver, G.; Holmes, K.;
Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.;
Miller, M.; Schleif, W. A.; Emini, E. A. Bioorg. Med.
Chem. Lett. 2004, 14, 941; (d) Shu, M.; Loebach, J. L.;
Parker, K. A.; Mills, S. G.; Chapman, K. T.; Shen, D.-M.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Siciliano, S. J.; Cascieri, M. A.; Carella, A.; Carver,
G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2004, 14, 946.
7. (a) Dorn, C. P.; Finke, P. E.; Oates, B.; Budhu, R. J.;
Mills, S. G.; MacCos, M.; Malkowitz, L.; Springer, M. S.;
Daugherty, B. L.; Gould, S. L.; DeMartino, J. A.;
Siciliano, S. J.; Carella, A.; Carver, G.; Holmes, K.;
Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.;
Miller, M.; Schleif, W. A.; Emini, E. A. Bioorg. Med.
Chem. Lett. 2001, 11, 259; (b) Finke, P. E.; Meurer, L. C.;
Oates, B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.;
Springer, M. S.; Daugherty, B. L.; Gould, S. L.; DeMar-
tino, J. A.; Siciliano, S. J.; Carella, A.; Carver, G.;
Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 255; (c) Finke, P. E.;
Meurer, L. C.; Oates, B.; Shah, S. K.; Loebach, J. L.;
Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer, M.
S.; Gould, S. L.; Demartino, J. A. Bioorg. Med. Chem.
Lett. 2001, 11, 2469; (d) Finke, P. E.; Meurer, L. C.; Oates,
B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver,
G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 2475; (e) Kim, D.;
Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver,
G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 3099; (f) Kim, D.;
Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver,
G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 3103; (g) Hale, J. J.;
Budhu, R. J.; Holson, E. B.; Finke, P. E.; Oates, B.; Mills,
S. G.; MacCoss, M.; Malkowitz, L.; Springer, M. S.;
Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver, G.;
Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 2741; (h) Caldwell, C.
G.; Chen, P.; Donnelly, K. F.; Finke, P. E.; Shankaran,
9. (a) Lipshutz, B. H.; Vaccaro, W.; Huff, B. Tetrahedron
Lett. 1986, 27, 4095; (b) Kunckell, F. Chem. Ber. 1901, 34,
637.
10. Moriya, O.; Takenaka, H.; Iyoda, M.; Urata, Y.; Endo, T.
J. Chem. Soc., Perkin Trans. 1 1994, 413.
11. (a) Bachstez, M. Chem. Ber. 1914, 47, 3163; (b) Goedon,
T. D.; Singh, J.; Hansen, P. E.; Morgan, B. A. Tetrahedron
Lett. 1993, 34, 1901; (c) Wasserman, H. H.; Lu, T. J.
Tetrahedron Lett. 1982, 23, 3831.
12. Siciliano, S. J.; Kuhmann, S. E.; Weng, Y.; Madani, N.;
Springer, M. S.; Lineberger, J.; Danzeisen, J.; Miller, M.
D.; Kavanaugh, M. P.; DeMartino, J. A.; Kabat, D.
J. Biol. Chem. 1999, 274, 1905.
13. The CCR5 binding IC50 results are an average of three
independent titrations having calculated standard errors
below 15%. The assay-to-assay variation was generally
2-fold.
14. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.;
Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabrylski,
L.; Schleif, W.; Blau, C.; Miller, M. D. Science 2000, 287,
646.
15. The reported HeLa antiviral IC90’s were generally the
result of a single experiment and are the lowest test
concentration for which >90% inhibition was observed.
The assay-to-assay variation of a standard test compound
was generally 3-fold.