Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: Structure-activity relationships for substituted 2-aryl-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes

Article abstract of DOI:10.1016/S0960-894X(00)00639-9

(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2 ,3-dihydrobenzthiophene-3,4′-piperidin-1′yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC₅₀ = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X = H, 3-F, 3-Cl, 3-Me).

Full text of DOI:10.1016/S0960-894X(00)00639-9

Bioorganic & Medicinal Chemistry Letters 11 (2001) 265±270
Antagonists of the Human CCR5 Receptor as Anti-HIV-1 Agents.
Part 2: Structure±Activity Relationships for Substituted 2-Aryl-1-
[N-(methyl)-N-(phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes
Paul E. Finke,a,* Laura C. Meurer,a Bryan Oates,a Sander G. Mills,a Malcolm MacCoss,a
Lorraine Malkowitz,b Martin S. Springer,b Bruce L. Daugherty,b Sandra L. Gould,b
Julie A. DeMartino,b Salvatore J. Siciliano,b Anthony Carella,b Gwen Carver,c
Karen Holmes,c Renee Danzeisen,c Daria Hazuda,c Joseph Kessler,c
Janet Lineberger,c Michael Miller,c William A. Schleifc and Emilio A. Eminic
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, PO Box 4, West Point, PA 19486, USA
Received 18 September 2000; accepted 9 November 2000
AbstractÐ(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,40-piperidin-10-
yl)]butane S-oxide (3) has been identi®ed as a potent CCR5 antagonist lead structure having an IC50=35 nM. Herein, we describe
the structure±activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The
phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16:
X=H, 3-F, 3-Cl, 3-Me). # 2001 Published by Elsevier Science Ltd.
Human immunode®ciency virus type-1 (HIV-1) is an
enveloped virus that must fuse its envelope with the
plasma membrane of its host cell to gain cell entry.1
CCR5, a seven-transmembrane receptor for the b-
chemokines MIP-1a, MIP-1b, and RANTES,2 has been
identi®ed as a primary co-receptor with CD4 for cell
entry of macrophage-tropic (M-tropic or R5) HIV-1
isolates.3 Individuals homozygous for a 32-base pair
deletion in the gene for CCR5 do not express functional
receptor on their cell surfaces and have been identi®ed
as being highly resistant to HIV-1 infection,4 while
infected individuals heterozygous for the defective gene
appear to exhibit delayed disease progression.5 Given
the importance of CCR5 for the establishment, and
possible maintenance, of HIV-1 infection in vivo, and
the lack of an overt detrimental phenotype in humans
that do not express functional CCR5, numerous e€orts
have been initiated in an e€ort to identify suitable
CCR5 antagonists for use as potential anti-HIV-1
therapeutic agents.6 9
Towards this end, there have now been several reports
of CCR5 antagonists in the patent literature.1,10 To
date, the most established structure is TAK-779 (1),11,12
which is actually a dual CCR5 and CCR2b antagonist
having binding anities of 1.4 and 27 nM, respectively.
In our ®rst manuscript in this series,13 the discovery of
several CCR5 selective (2S)-1-(N-alkyl-N-arylsulfonyl-
amino)-2-phenyl-4-(piperidin-1-yl)butane structures (2)
were identi®ed through screening of the Merck sample
collection and our initial structure±activity relationships
(SARs) pertaining to the C-1 N-alkyl-N-arylsulfonamide
moiety of 2 were reported. This work resulted in the iden-
ti®cation of (2S)-2-(3,4-dichlorophenyl)-1-[(N-methyl-
N-phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthio-
phene-3,40-piperidin-10-yl)]butane S-oxide (3, mixture of
R and S-sulfoxides) as our initial key lead structure
having an IC50=35 nM for inhibition of [125I]-MIP-1a
*Corresponding author. E-mail: paul_®nke@merck.com
0960-894X/01/$ - see front matter # 2001 Published by Elsevier Science Ltd.
PII: S0960-894X(00)00639-9

266
P. E. Finke et al. / Bioorg. Med. Chem. Lett. 11 (2001) 265±270
binding to CCR5.14 Herein, the SAR for the central
C-2-phenyl moiety will be described.
Using chemistry similar to that reported previously
from these laboratories13,15,16 (see Scheme 1) and several
of the available intermediates, an initial SAR for the
central phenyl ring was rapidly developed that indicated
substitution on the phenyl could dramatically e€ect
CCR5 inhibition, monosubstitution at the 3-position
being preferred (see Table 1, compound 13d). In addition,
some early work on other piperidine derivatives indicated
that the 4-phenylpiperidine as in 4 could replace the spiro-
piperidine of 3 while retaining most of the CCR5 binding
potency, but with a greatly simpli®ed structure.
Thus, in order to more easily explore the central phenyl
ring substitution, a modi®ed synthetic approach (see
Scheme 2) was developed which could introduce a sub-
stituted aryl group at C-2 late in the synthesis rather than
in the starting material as required in our established
route. This new approach utilized an appropriately di-
functionalized vinyl±tin intermediate 20, which under-
went Pd-catalyzed coupling17 with a variety of aryl
bromides to give the substituted styrenes 22. Subsequent
hydrogenation a€orded the ®nal racemic compounds in
only two steps. The simpli®ed piperidine moiety from
above was employed in this alternate tin-coupling route.
to a€ord the desired chiral (2S) enantiomer 6a. Use of
(R)-(+)-a-methylbenzylamine a€orded the (2R) enantio-
mer 6b. Alternatively, chemical resolution was possible by
conversion of 6 to the diastereomeric (S)-( )-4-benzyl-2-
oxazolidinone derivatives, separation on silica gel, and
hydrolysis with lithium hydroxide/hydrogen peroxide in
THF.16 Thus, the C-2 stereochemistry and phenyl sub-
stitution were set at the start. Conversion of 6a to the
amides 7 was done via the acid chlorides followed by
treatment with methylamine. Reduction of 7 with DIBAL-
H provided the N-methylamine intermediates 8, which
The synthesis of 3 and several initial substituted C-2
phenyl derivatives (Scheme 1) began with the phenylacetic
acids 5. Alkylation of 5 with allyl bromide using lithium
hexamethyldisilylamide (LiHMDS) provided racemic 6
that, if desired, could usually be resolved by repeated
crystallization of the (S)-( )-a-methylbenzylamine salts
Scheme 1. Reagents: (a) LiHMDS, THF, 70ꢀC; (b) allyl bromide, 70ꢀC to rt; (c) (S)-( )-a-methylbenzylamine (0.6 equiv), i-PrOH, then two recrys-
tallizations a€ords 6a; (d) (R)-(+)-a-methylbenzylamine (1 equiv), i-PrOH, then two recrystallizations a€ords 6b; (e) 2 N HCl, water, EtOAc (three
extractions); (f) (Me3CCO)2O, TEA, THF, 70ꢀC to rt, then lithium salt of (S)-4-benzyl-2-oxazolidine in THF, 70ꢀC to rt; (g) LiOH, H2O2, 2:1 v/v
THF/water, 0 ꢀC, then Na2SO3 (aq), rt; (h) oxalyl chloride, DMF (cat), DCM, rt; (i) MeNH2 (40% aq, 5 equiv), THF, 0 ꢀC to rt; (j) DIBAL-H, THF,
rt; (k) PhSO2Cl, DIPEA, DCM, rt; (l) OsO4 (cat), NMO, 2:1:1 v/v/v acetone/t-butanol/water, rt; (m) NaIO4, 4:1 v/v THF/water, rt; (n) 11-HCl, DIPEA,
NaBH(OAc)3, DCE, rt; (o) Oxone1 (1.2 equiv), MeOH, 20ꢀC, 2±5min; (p) Oxone1 (3 equiv), MeOH, rt; (q) 15, AcOH, NaBH(OAc)3, DCE, rt.

P. E. Finke et al. / Bioorg. Med. Chem. Lett. 11 (2001) 265±270
267
were then sulfonylated with benzenesulfonyl chloride to
a€ord the functionalized right hand portion (9). A two-
step oxidation of the allyl group with osmium tetroxide/N-
methylmorpholine-N-oxide (NMO) followed by sodium
periodate cleavage of the intermediate diols a€orded the
aldehydes 10. Reductive amination18 of the spiro-
piperidine 11 with 10 using sodium triacetoxyborohy-
dride in dichloroethane (DCE) provided the sul®de deri-
vatives 12a±k. Final oxidation of the sulfur with 1 equiv of
Oxone119 at 20 ꢀC a€orded the sulfoxides 3 and 13b±k
(as 1:1 mixtures of sulfoxide diastereomers), while oxida-
tion with excess Oxone1 at room temperature a€orded the
corresponding sulfones 14a±k (see Table 1). Alternatively,
reductive alkylation of 4-phenylpiperidine (15) with alde-
hydes 10 resulted in the corresponding substituted central
phenyl derivatives 16a±k (see Table 2).
Table 1. Structures and CCR5 binding activities for the spiro-
piperidine derivatives 3, 12, 13, and 14
Since the activities of the above 4-phenylpiperidine deri-
vatives had only a 3-fold or less reduction in CCR5
binding anity compared to the corresponding sulfoxide
compounds (see below), this simpli®ed left-hand moiety
was utilized for further exploration of the central phenyl
in the following modi®ed synthetic route (Scheme 2). 2-
Butyn-1,4-diol (17) was treated with 2.5 equiv of tri-
phenylphosphine-dibromide to form the dibromide 18.
In a one-pot double displacement sequence, ®rst with
0.75 equiv of the preformed sodium salt of N-methyl-
benzenesulfonamide followed by excess 4-phenylpiperi-
dine (15), the crude 18 a€orded the disubstituted alkyne
19 in 42% yield. Hydrostannylation20 of 19 was carried
out with PdCl2(Ph3P)2 in THF to give primarily the
desired readily separable regioisomer 20 over 21 in a 4:1
ratio (55 and 17%, 32% recovered 19).21 The best con-
ditions found for the coupling of 20 to a variety of sub-
stituted phenyl bromides and 2- and 3-bromopyridine
utilized PdCl2(Ph3P)2 in N-methylpyrrolidine (NMP) at
70 ꢀC in the presence of potassium carbonate. The
inclusion of potassium carbonate neutralized any acid
formed and served to provide a more reactive ligand for
the Pd.17 Yields of the coupled styrene products 22 were
between 20 and 40%. Hydrogenation of 22 to the ®nal
racemic products 16 was done with Pd(OH)2 in meth-
anol and required the addition of acetic acid. Unfort-
unately, these conditions also promoted the partial
hydrogenolysis of the allylic piperidine to give 23 and
resulted in lower yields of 16, usually about 50%. The
Structure
R
CCR5a
Compound
n
IC50 (nM)b
12a
3
0
1
2
0
1
2
1
2
0
1
2
1
1
1
2
1
2
1
2
1
2
1
2
(S)-3,4-diCl-Phenyl
(S)-3,4-diCl-Phenyl
(S)-3,4-diCl-Phenyl
(R/S)-Phenyl
(R/S)-Phenyl
(R/S)-Phenyl
(R/S)-2-Cl-Phenyl
(R/S)-2-Cl-Phenyl
(S)-3-Cl-Phenyl
(S)-3-Cl-Phenyl
(S)-3-Cl-Phenyl
(S)-4-Cl-Phenyl
(S)-4-F-Phenyl
1000
35
100
450
35
30
2000
1300
270
10
15
270
570
90
110
200
14a
12b
13b
14b
13c
14c
12d
13d
14d
13e
13f
13g
14g
13h
14h
13i
(R/S)-3,5-diCl-Phenyl
(R/S)-3,5-diCl-Phenyl
(S)-3,4-OCH2O-Phenyl
(S)-3,4-OCH2O-Phenyl
(R/S)-2-Thienyl
80
180
110
100
14i
13j
14j
13k
14k
(R/S)-2-Thienyl
(R/S)-3-Thienyl
(R/S)-3-Thienyl
(R/S)-Cyclohexyl
(R/S)-Cyclohexyl
50
>1000 (36%)c
>1000 (42%)c
aSee ref 13 for procedures.
bThe IC50 results are an average of three independent titrations having
calculated standard errors below 15%. The assay-to-assay variation was
generally Æ2-fold based on the results of the standard compound 13d.
cThese compounds gave the indicated % inhibition at 1000 nM.
Scheme 2. Reagents: (a) (Ph3P)-Br2 (2.25 equiv), MeCN, 0 ꢀC to rt; (b) PhSO2NHMe (0.75 equiv), NaH (60%), DMF, 0 ꢀC; (c) crude 18 in DMF,
0 ꢀC, addition of PhSO2NMe-Na (0.75 equiv) from (b), 0 ꢀC, 2 h; then 15 (1.5 equiv), DIPEA, rt; (d) Bu3SnH, PdCl2(Ph3P)2 (2 mol%), THF, rt;
(e) X-PhBr, PdCl2(Ph3P)2 (3 mol%), K2CO3, N-methylpyrrolidine, 70 ꢀC, 16 h; (f) H2 (50 psi), 20% Pd(OH)2 (cat), HOAc, MeOH, rt.

268
P. E. Finke et al. / Bioorg. Med. Chem. Lett. 11 (2001) 265±270
Table 2. Structures and CCR5 binding activities for the 4-phenyl-
piperidine derivatives 16 and 27
Structure
R
CCR5a
IC50 (nM)b
Compound
16b
16c
16d
16f
16g
16h
16i
16j
16k
16l
16m
16n
16o
16p
16q
16r
16s
16t
16u
16v
16w
16x
16y
16z
16aa
27a,b
(R/S)-Phenyl
(R/S)-2-Cl-Phenyl
(S)-3-Cl-Phenyl
120
3000
Scheme 3. Reagents: (a) Bu3SnH, PdCl2(Ph3P)2 (2mol%), THF, rt; (b)
benzyl bromide, PdCl2(Ph3P)2 (3mol%), K2CO3, NMP, 70ꢀC, 6 h; (c)
(Ph3P)-Br2 (2.25 equiv), MeCN, 0 ꢀC to rt; (d) PhSO2NHMe (0.75
equiv), NaH (60%), DMF, 0 ꢀC; (e) crude dibromide in DMF, 0 ꢀC,
addition of PhSO2NMe-Na (0.75 equiv) from (d), 0 ꢀC, 2 h; then 15 (1.5
equiv), DIPEA, rt; (f) H2 (50 psi), 20% Pd(OH)2, HOAc, MeOH, rt.
30
ꢁ1000
(S)-4-F-Phenyl
(R/S)-3,5-diCl-Phenyl
(S)-3,4-OCH2O-Phenyl
(R/S)-2-Thienyl
300
300
400
100
(R/S)-3-Thienyl
(R/S)-Cyclohexyl
(R/S)-3-F-Phenyl
(R/S)-3-Me-Phenyl
(R/S)-3-Et-Phenyl
(R/S)-3-CF3-Phenyl
(R/S)-3-OMe-Phenyl
(R/S)-3-Biphenyl
(R/S)-4-Me-Phenyl
(R/S)-4-OMe-Phenyl
(R/S)-3,5-diMe-Phenyl
(R/S)-3,4-diF-Phenyl
(R/S)-3,4-diMe-Pphenyl
(R/S)-3-Me,4-F-Phenyl
(R/S)-3-F,4-Me-Phenyl
(R/S)-2-Pyridyl
>1000 (26%)c
100
80
110
500
>1000 (45%)c
ꢁ10,000 (76%)d
200
>1000 (40%)c
160
570
60
180
Scheme 4.
110
ꢁ10,000 (61%)d
>10,000 (43%)d
720
(R/S)-3-Pyridyl
(R/S)-2-Naphthyl
(R/S) Benzyl
positions resulted in a clear preference for substitution
at the 3-position as seen in the chloro sulfoxide series 13c,
13d, and 13e (IC50=2000, 10 and 270 nM, respectively).
In agreement with previous results with 12a, 3, and 14a,13
in all cases the sul®des had the poorest CCR5 binding
anity (i.e. 12b and d, IC50=450 and 270 nM) while the
sulfone derivatives usually resulted in only slightly poorer
binding than the corresponding sulfoxides (compare 13c
and 14c, 10 and 15nM, respectively). Thus, the following
discussion deals mostly with the sulfoxide results. While
it would have been of interest, any possible sulfoxide
stereochemical preference for CCR5 interaction was not
determined since the sulfoxide isomers were not separ-
able. In agreement with the improved CCR5 binding seen
with 13d and 14d, enhanced antiviral activity was also
observed (see below).
ꢁ10,000 (68%)d
aSee ref 13 for procedures.
bThe IC50 results are an average of three independent titrations having
calculated standard errors below 15%. The assay-to-assay variation was
generally Æ2-fold based on the results of the standard compound 13d.
cThese compounds gave the indicated % inhibition at 1000 nM.
dThese compounds gave the indicated % inhibition at 10,000 nM.
®nal compounds 16l±aa prepared by this route are also
listed in Table 2.
In order to prepare the C-2 benzyl derivative, the reac-
tion of 20 with benzyl bromide was attempted. However,
alkylation of the piperidine nitrogen occurred to give the
quaternary amine. Thus, a modi®ed route was utilized
starting from the diol 17 (Scheme 3). Using analogous
chemistry as above, the vinyl stannane 24 a€orded
2-benzylbut-2-ene-1,4-diol (25). The incorporation of
the sulfonamide and piperidine moieties was again
achieved in a single reaction via the dibromide to a€ord
26a,b. Final hydrogenation then a€orded 27a,b as a
mixture of racemic regioisomers.
Removal of both of the chlorines as in 13b
(IC50=35 nM, racemic22) actually resulted in a possible
2-fold improvement in binding compared to the 3,4-
dichloro lead compound 3 (IC50=35 nM, chiral22) and
within a 2-fold reduction compared to 13d. Dichloro
substitution at the 3,5-positions (13g, IC50=90 nM, rac-
emic) was not additive and actually showed a moderate
loss in potency compared to 13d. 3,4-Disubstitution as in
the methylenedioxy derivative 13h (IC50=200nM, chiral)
decreased anity relative to 3. Replacement of the
phenyl with either a 2- or 3-thienyl (13i and 13j, 180 and
100 nM, both racemic) led to a moderate loss in binding
while the cyclohexane analogue 13k resulted in very poor
activity. Thus, from this initial survey of substitutions on
the C-2 phenyl, limited substitution at the 3-position or
even no substitution appeared to be preferred.
Finally, use of the isomeric stannane 21 a€orded the
isomerically pure racemic C-3 phenyl derivative 28 and
hydrogenation of the alkyne 19 yielded the des-phenyl
derivative 29 (Scheme 4).
These compounds were then evaluated for CCR5 a-
nity utilizing a [125I]-MIP-1a binding assay.14 An initial
survey of monosubstitution at the 2-, 3-, and 4-phenyl

P. E. Finke et al. / Bioorg. Med. Chem. Lett. 11 (2001) 265±270
269
From our initial screening results, there had been hints
that the spiro-piperidine was not required and that a
simple 4-phenylpiperidine might have similar binding
(data not shown). Indeed, this modi®cation in the above
cases a€orded very similar results, being within a factor
of three in all cases as exempli®ed with the best 3-chloro
compounds 13d and 16d having IC50s of 10 versus
30 nM. Also, the unsubstituted compound 16b was only
2-fold lower in binding than 16d, the best 3-substituted
compound in this series (IC50=120 nM, racemic, versus
30 nM chiral). Thus, this simpli®ed piperidine derivative
was utilized in a more rigorous exploration of the
phenyl substitution. From these additional derivatives,
other small substituted analogues, such as 3-¯uoro (16l,
IC50=100 nM, racemic), 3-methyl (16m, IC50=80 nM,
racemic), and even 3-ethyl (16n, IC50=110 nM, race-
mic), exhibited potency within 2-fold of 16d. Larger
groups, such as tri¯uoromethyl (16o), methoxy (16p),
and phenyl (16q), all had diminished CCR5 anity.
Surprisingly, the binding of the 4-methyl compound 16r
(IC50=200 nM, racemic) was appreciably better than
would be expected from the 4-Cl (13e) and 4-F (13f
and 16f) results, although the 4-MeO compound (16s)
was inactive. The benign e€ect of the 4-methyl carried
over to the 3,4-dimethyl derivative (16v, IC50=60 nM,
racemic), which appeared to be equipotent with the
3-chloro 16d, as well as the 3-F,4-Me compound
16x (IC50=110 nM, racemic). However, other 3,4-di-
substitution was generally detrimental as anticipated (see
16u and 16w). Replacement of the central phenyl ring
with a 2- or 3-pyridyl (16y and 16z) resulted in sub-
stantial loss of CCR5 activity. Extension of the phenyl
by a methylene unit was not tolerated as seen with the
benzyl derivatives 27a,b for which there was no appar-
ent activity for any of the four isomers. All the vinyl
intermediates 22 and the des-piperidine compound 23
were inactive (Scheme 2, IC50>4000 nM, data not shown).
The importance of the phenyl was also demonstrated by
the lack of CCR5 anity for the C-3 phenyl isomer 28 and
the des-phenyl compounds 19 and 29 (61, 5, and 20% I at
10,000nM, respectively).
YU-2 strain. As expected, 13d failed to give any inhibi-
tion when the X4-tropic NL4-3 strain was used (data
not shown).
Herein, the results of our SAR study of the central
phenyl ring of lead compound 3 were described. In the
spiro-piperidine series, the 3-chloro derivative 13d was
identi®ed as a having a 4-fold improvement in CCR5
binding anity and resulted in enhanced antiviral inhi-
bition in a PBMC based assay with an IC95 as low as
1500 nM and served thereafter as a standard in this
assay.24 Selectivity for CCR5 was maintained by 13d in
that the IC50's for CCR1, CCR2, CCR3, and CXCR4
were all >10,000 nM. Both 13d and 14d showed modest
pharmacokinetics in the rat at 1 mg/kg iv and 10 mg/kg
oral (t1/2=0.7 and 0.8 h, F=3 and 2%, respectively). In
addition, the unsubstituted compound 13b was found to
be nearly as potent an antagonist as 13d and 14d.
Comparable anity was also found in the 4-phenyl-
piperidine series which allowed identi®cation of other
small substituents, such as 3-F (16i) and 3-Me (16m), as
being nearly equipotent to 3-Cl. These results allowed
the simpli®cation of the synthesis of further piperidine
derivatives as well as other structural modi®cations
which will be reported in the future.
References and Notes
1. For a review of HIV-1 entry mechanisms and current inhi-
bitors, see: Blair, W. S.; Lin, P.-F.; Meanwell, N. A.; Wallace,
O. B. Drug Discovery Today 2000, 5, 183.
2. For a recent chemokine review, see Baggiolini, M.; Dewald,
B.; Moser, B. Annu. Rev. Immunol. 1997, 15, 675.
3. For a review of the co-receptor search, see: Fauci, A. S.
Nature 1996, 384, 529.
4. 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. L.; Chang, G.; Louie, L. G.; Mascola, J. R.;
Dondero, D.; Birx, D. L.; Sheppard, H. W. Nature Med. 1997,
3, 338.
6. Bates, P. Cell 1996, 86, 1.
7. Moore, J. P. Science 1997, 276, 51.
8. Cohen, O. J.; Kinter, A.; Fauci, A. S. Immunol. Rev. 1997,
159, 31.
9. D'Souza, M. P.; Cairns, J. S.; Plaeger, S. F. JAMA 2000,
284, 215.
10. Horuk, R.; Ng, H. P. Med. Res. Rev. 2000, 2, 155.
11. Shiraishi, M.; Aramaki, Y.; Seto, M.; Imoto, H.; Nishi-
kawa, Y.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishi-
mura, O.; Baba, M.; Fujino, M. J. Med. Chem. 2000, 43, 2049.
12. Dragic, T.; Trkola, A.; Thompson, D. A. D.; Cormier,
E. G.; Kajumo, F. A.; Maxwell, E.; Lin, S. W.; Ying, W.;
Smith, S. O.; Sakmar, T. P.; Moore, J. P. Proc. Natl. Acad.
Sci. U.S.A. 2000, 97, 5639.
13. Dorn, C. P.; Finke, P. E.; Oates, B.; Budhu, R. J.; Mills,
S. G.; MacCoss, M.; Malkowitz, L.; Springer, M. S.; Daughtery,
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.
The lead structure 3 was initially characterized in an iso-
lated peripheral blood mononuclear cell (PBMC) viral
replication assay23 using the R5-tropic HIV-1 YU-2 iso-
late and gave IC95 values of 6 to 12 mM.13 This activity
indicated that inhibition of viral entry was possible with
these small molecule CCR5 antagonists. With the
enhancement in the CCR5 binding assay obtained with
the 3-chlorophenyl derivative 13d in the spiro-piperidine
series, better results were also seen in this antiviral assay,
giving an IC95 as low as 1500 nM,24 while the sulfone 14d
a€orded an IC95 of 3000 nM in the same assay. Use of
the di€erent R5-tropic strain SF162 a€orded IC95's of
800 and 6000 nM for 13d and 14d, respectively. The
unsubstituted compound 13b also a€orded inhibition
similar to 13d in the same assay. The best thiophene
derivative (14j, IC50=50 nM) was not active in this
assay (IC95>25,000 nM). As expected from the CCR5
binding data, the antiviral activity was poorer in the
4-phenylpiperidine series, again the best activity was
seen with the 3-chloro derivative 16d, as well as the 3-
methyl 16m, both having IC95 of 6000 nM against the
14. For a description of the binding assay, see ref 13, footnote
25. The CCR5 binding titrations were usually done in tripli-
cate with standard errors of <15%. Assay-to-assay variability
was generally Æ2-fold based on the standard compound 13d.

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P. E. Finke et al. / Bioorg. Med. Chem. Lett. 11 (2001) 265±270
1
15. MacCoss, M.; Mills, S. G.; Shah, S. K.; Chiang, Y.-C. P.;
Dunn, P. T.; Koyama, H. US Patent 6,013,652, 2000; Chem.
Abstr. 2000, 132, 78470s.
16. Hale, J. J.; Finke, P. E.; MacCoss, M. Bioorg. Med. Chem.
Lett. 1993, 3, 319.
17. For reviews of the Stille coupling, see: (a) Stille, J. K.
Angew. Chem., Int. Ed. Engl. 1986, 25, 508; or (b) Stille, J. K.
Pure Appl. Chem. 1985, 57, 1771.
18. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Mary-
ano€, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
19. Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
20. Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem.
1990, 55, 1857.
21. NMR data for the isomeric stannanes 20 and 21. Higher
Rf product 20: 1H NMR (400 MHz, CDCl3) d 0.8±0.9 (m, 6H),
0.87 (t, J=7 Hz, 9H), 1.25±1.35 (m, 6H), 1.35±1.5 (m, 6H),
1.6±1.85 (2 m, 4H), 1.94 (dt, J=3 and 8 Hz, 2H), 2.43 (m, 1H),
2.69 (s, 3H), 3.01 (brt, JH Sn=25 Hz, 2H), 3.78 (d, J=6 Hz,
2H), 5.44 (brt, J=1.5 and 6 Hz, JH Sn=34 Hz, 1H), 7.1±7.3 (2
m, 5H), 7.5±7.65 (m, 3H), 7.77 (dd, J=1.5 and 7.0 Hz, 2H).
Lower Rf product 21: H NMR (400 MHz, CDCl3) d 0.87 (t,
J=7 Hz, 9H), 0.95±1.05 (m, 6H), 1.25±1.4 (m, 6H), 1.45±1.6
(m, 6H), 1.7±1.85 (m, 4H), 1.92 (dt, J=3 and 8 Hz, 2H), 2.42
(m, 1H), 2.48 (s, 3H), 2.96 (m, 2H), 3.74 (brt, JH Sn=23 Hz,
2H), 5.88 (brt, J=6 Hz, JH Sn=32 Hz, 1H), 7.1±7.3 (2 m, 5H),
7.5±7.65 (m, 3H), 7.77 (dd, J=1.5 and 7.0 Hz, 2H).
22. Since the C-2 (R) con®guration was much less potent than
the (S),13 for comparison with chiral derivatives the e€ective
IC50 activities for the racemic derivatives can be assumed to be
essentially half that indicated in the tables.
23. Condra, J. H.; Schleif, W. A.; Blahy, O. M.; Gabryelski,
L. J.; Graham, D. J.; Quintero, J. C.; Rhodes, A.; Robbins,
H. L.; Roth, E.; Shivaprakash, M.; Titus, D.; Yang, T.; Tep-
pler, H.; Squires, K. E.; Deutsch, P. J.; Emini, E. A. Nature
1995, 374, 569.
24. There was extensive variation in the results from this
PBMC assay as seen in the results for 13d, which varied from
1500 to 12,500 nM. Thus, 13d was always used as a standard
and the results for the other compounds are reported in rela-
tion to the result for 13d in the same assay.