2-arylindole-3-acetamides: FPP-competitive inhibitors of farnesyl protein transferase

Article abstract of DOI:10.1016/S0960-894X(01)00061-0

A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.

Full text of DOI:10.1016/S0960-894X(01)00061-0

Bioorganic & Medicinal Chemistry Letters 11 (2001) 865–869
2-Arylindole-3-acetamides:
FPP-Competitive Inhibitors of Farnesyl Protein Transferase
B. Wesley Trotter,a,* Amy G. Quigley,a William C. Lumma,a John T. Sisko,a
Eileen S. Walsh,b Christian S. Hamann,b Ronald G. Robinson,b
Hema Bhimnathwala,b D. Garrett Kolodin,c Wei Zheng,c Carolyn A. Buser,b
Hans E. Huber,b Robert B. Lobell,b Nancy E. Kohl,b Theresa M. Williams,a
Samuel L. Grahama and Christopher J. Dinsmorea
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Cancer Research, Merck Research Laboratories, West Point, PA 19486, USA
cDepartment of Automated Biotechnology, Merck Research Laboratories, West Point, PA 19486, USA
Received 1 December 2000; accepted 15 January 2001
Abstract—A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit
the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related
enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-
2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed. # 2001 Published by Elsevier Science Ltd.
Inhibition of the cellular enzyme farnesyl protein trans-
ferase (FPTase) has emerged in recent years as a poten-
tially effective strategy for cancer treatment. The
observation that Ras prenylation, a primary function of
FPTase, is essential to membrane localization of Ras
and subsequent propagation of growth-promoting sig-
nals has prompted a number of investigators to design
and synthesize selective, small molecule farnesyl protein
transferase inhibitors (FTIs).1 Further studies of FTIs
and their biological activities have painted an increas-
ingly complex picture of the effects of these compounds
on cells.2,3 Importantly, two of three Ras isoforms
found in human cells can be alternatively prenylated by
the enzyme geranylgeranyltransferase-I (GGPTase-I) in
the absence of FPTase activity,4 and non-Ras substrates
for FPTase have been discovered.5
C-terminal Ca1a2X peptide binding motif; (b) farnesyl
pyrophosphate (FPP) competitive compounds, which
displace the second FPTase substrate; and (c) bisub-
strate inhibitors designed to occupy the peptide and
FPP binding sites simultaneously.1
Given the existence of at least 18 FPTase protein sub-
strates in mammalian cells,2 inhibitors that compete
only with FPP offer the potential advantage of protein
substrate-independent enzyme inhibition. A number of
small molecule FPP-competitive FTIs have been
designed,7 the majority by farnesylpyrophosphate
mimicry8 or by modification of previously identified
inhibitors of the FPP-utilizing enzyme squalene syn-
thase.9 Here we report the identification of a unique
series of FPP-competitive FTIs, 2-arylindole-3-acet-
amides,10 which were developed from a high-through-
put screen for FPTase inhibition.
Despite such considerations, FTIs have shown promis-
ing early results as antitumor agents in human clinical
trials.6 FTIs reported to date can be broadly classified
under three headings: (a) protein-competitive inhibitors,
which occupy the FPTase site that normally accepts a
Arylindole 1 is highly selective for inhibition of FPTase
(IC50 106 nM) over the related prenyltransferase
GGPTase-I (IC50 GGPTase-I >20,000 nM). The mode
of FPTase inhibition by 1 was qualitatively determined
by observation of FPP- and CaaX-dependent modula-
tions of inhibitory potency (Table 1). While variation of
peptide substrate concentration had no effect on
*Corresponding author. Fax: +1-215-652-7310; e-mail: bwesley_trotter@
merck.com
0960-894X/01/$ - see front matter # 2001 Published by Elsevier Science Ltd.
PII: S0960-894X(01)00061-0

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B. W. Trotter et al. / Bioorg. Med. Chem. Lett. 11 (2001) 865–869
FPTase inhibition by 1, increasing IC50 values were
measured as the FPP concentration was raised from 20
to 500 nM.
Variation of the amide N-alkyl substituent was exam-
ined in the context of both 4- and 3-pyridylmethyl
amides (Table 2).16 Isopropyl amides 7a and 7b exhib-
ited increased FPTase activity relative to 1. Cyclopropyl
and cyclobutyl substituents were well-tolerated in com-
bination with the 3-pyridylmethyl substituent (8b and
9b) but caused a drop in potency when combined with
the 4-pyridylmethyl group (8a and 9a).17
In these experiments, we also observed a significant
anion effect on inhibitory activity. For instance, while
the mode of inhibition was anion-independent, con-
sistently lower IC50 values were measured in the presence
of 5 mM ATP (Table 1). This effect could be reproduced
by the addition of various inorganic anions, including
inorganic phosphate and sulfate.11 A similar phenom-
enon has been observed previously in a structurally dis-
tinct class of FPP-competitive FPTase inhibitors.7,12
Larger substituents such as isobutyl and cyclopentyl (10
and 11) effected significant losses in potency. Bis(pyr-
idylmethyl) N-substitution also resulted in decreased
potency (14). sec-Butyl substituted enantiomers (S)-12
and (R)-13 exhibited a 50-fold difference in potency
indicative of a stereospecific binding interaction for the
N-alkyl substituent.
Structure–Activity Relationships: In Vitro Potency
Initial development of lead 1 focused on exploration
of amide N-substituent structure–activity relationships.
Rapid preparation of the appropriate compounds was
possible via coupling reactions of commercially avail-
able acid 5 and various secondary amines (e.g., 4,
Scheme 1). The amines were obtained either from com-
mercial sources or by reductive alkylation (NaBH4,
MeOH) of primary amines (2+3!4, Scheme 1).
While 4- and 3-pyridylmethyl amides 7a and 7b were
potent FPTase inhibitors, 2-pyridylmethyl isomer 7c
was an order of magnitude less active (Table 3). Other
heterocyclic replacements, including pyrazine, furan,
and pyrazole, were tolerated but exhibited somewhat
reduced potencies. Replacement of the N-heteroaryl-
methyl substituent with nonaromatic groups was only
successful in limited cases (vide infra).
Investigation of SARin the 2-aryl region was accom-
plished using the synthesis strategy depicted in Scheme 2.
Bromination18 of 3-indolyl-acetonitrile was followed by
Suzuki coupling with various boronic acids. Cyano
hydrolysis and subsequent peptide coupling provided
access to the desired compounds.
Table 1. Mode of FPTase inhibition by 1
1
FPTase IC50 106 nMa
GGTase-I IC50>20000 nMb
The 2-aryl region is largely intolerant to alteration
(Table 4). Substitution at either the para or meta
position of this aromatic ring was poorly tolerated
(20d, 20e).19 In contrast, substitution at the ortho
position of the 2-aryl ring was accommodated in certain
cases. ortho-Chloro and ortho-methyl analogues 20a
and 20b were as potent as the parent 7a, but polar
substitution at the ortho-position was not tolerated (20c,
Table 4).
Peptidec
(nM)
FPP
FPTase
Peptidec
(nM)
FPP
(nM)
FPTase
IC50 (nM)d
(nM) IC50 (nM)d
20
100
500
100
100
100
47 (230)
43 (250)
65 (230)
100
100
100
20
100
500
20 (54)
43 (250)
190 (4000)
aConcentration of compound required to reduce the human FPTase-
catalyzed incorporation of 3H FPP into recombinant Ras-CVIM by
50% in the presence of 5 mM ATP (ref 13).
bConcentration of compound required to reduce the human
GGPTase-I-catalyzed incorporation of 3H GGPP (100 nM) into a
biotinylated K-Ras-derived peptide (1.6 mM, note c) by 50% (ref 14).
cBiotinylated peptide corresponding to the C-terminus of human K-
Ras (b-GKKKKKKSKTKCVIM, Research Organics).
Table 2. Variation of the amide N-alkyl substituent
dConcentration of compound required to reduce the human FPTase-
catalyzed incorporation of 3H FPP into a biotinylated K-Ras-derived
peptide (note c) by 50% in the presence of 5 mM ATP (ref 15); values
in parentheses were obtained without addition of ATP.
Compound
RIC
Compound
RIC
50
(nM)a
50
(nM)a
7a
8a
9a
10a
11a
12
Isopropyl
Cyclopropyl
Cyclobutyl
Isobutyl
Cyclopentyl
(S)s-Butyl
(R)s-Butyl
41
171
160
3900
4004
77
7b
8b
9b
10b
11b
14
Isopropyl
Cyclopropyl
Cyclobutyl
Isobutyl
Cyclopentyl 11389
3-Py-Methyl
1-CN-Ethyl
58
45
44
2484
2733
380
13
4588
15
Scheme 1. Conditions: (a) NaBH4, MeOH; (b) PyBOP, iPr2EtN,
DMF.
aSee footnote a in Table 1.

B. W. Trotter et al. / Bioorg. Med. Chem. Lett. 11 (2001) 865–869
867
Removal of the 2-aryl moiety results in complete loss of
potency (21a). This potency can be partially recovered
by attachment of a benzyl group to the indole nitrogen
(Table 4). Introduction of substituents on the benzyl
group exerts significant effects on potency; the ortho-
bromo substituted compound 21c is the most active in
this class. In FPTase-bound conformations, the N-ben-
zyl group found in 21b–e may therefore occupy the
same space as the 2-aryl moiety common to 1–20.
N-Cyanoethyl-N-cyclopropyl amides 23 are among the
few examples we have found of non-arylmethyl amides
that retain in vitro potency against FPTase (Table 5).
Comparison of the SARdelineated above with the
dataset obtained for the cyanoethyl analogues 23 again
indicates that the contributions to potency of different
regions of the molecule are nonadditive. Methylation of
the indole 1-position in this series does not increase
potency (contrast 23a/23b and 7a/22b). Likewise, ortho-
substitution of the 2-aryl group in this series is not well
tolerated (23c,d). This tight interplay among substituent
patterns may be a further indication of highly restrictive
requirements for binding to FPTase.22
Substitution of the remaining positions on the indole
nucleus was next examined. Methyl substitution at any
of the 4–7 positions of the indole nucleus20 resulted in
substantial loss of FPTase potency. In contrast,
alkylation of the indole nitrogen21 (Table 4) provided
N-methyl derivatives 22a and 22b, the most potent
compounds synthesized to date in the 2-arylindole-3-
acetamide series. Homologation to the N-ethyl deriva-
tive 22c resulted in a dramatic decrease in potency, and
higher homologues were less potent still.
Inhibition of Protein Processing in Cell-Based Assays
Inhibitors 22a and 22b were selected for further evalua-
tion in cell-based assays. Both compounds inhibited the
Table 4. Modifications of the 2-arylindole core
Table 3. FPTase inhibition by heterocyclic variants of 1
Compound
R1
R2
IC50 (nM)a
20a
20b
20c
20d
20e
2-Cl-Ph
2-Me-Ph
2-MeO-Ph
3-Cl-Ph
H
H
H
H
H
46
31
1372
172
Compound
Het
IC50
(nM)a
Compound
Het
IC50
(nM)a
4-Br-Ph
14,369
7a
7b
7c
7d
7e
41
58
7f
7g
7h
7i
232
400
245
527
568
21a
21b
21c
21d
21e
H
H
H
H
H
H
Bn
2-Br-Bn
3-Br-Bn
4-Br-Bn
>50,000
8685
572
2150
1740
684
110
241
22a
22b
22c
22d
22e
2-Me-Ph
Ph
Ph
Me
Me
Et
n-Pr
n-Bu
12
15
3803
29,863
>50,000
Ph
Ph
aSee footnote a in Table 1.
7j
aSee footnote a in Table 1.
Table 5. Cyanoethyl replacement of the amide N-arylmethyl sub-
stituent
Compound
R1
R2
IC50 (nM)a
23a
23b
23c
23d
23e
H
Me
H
H
H
H
H
Me
Cl
123
182
712
1628
8641
Scheme 2. Conditions: (a) N-bromosuccinimide, silica gel, CH2Cl2; (b)
Ar-B(OH)2, LiCl, Na2CO3, Pd(PPh3)4, toluene; (c) NaOH, MeOH/
H2O; (d) isopropyl 4-pyridylmethylamine, PyBOP, iPr2EtN, DMF.
OMe
aSee footnote a in Table 1.

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B. W. Trotter et al. / Bioorg. Med. Chem. Lett. 11 (2001) 865–869
Table 6. Inhibition of HDJ-2 and K-Ras processing in PSN-1 cellsa
Acknowledgements
Compound
GGTIb
(nM)
HDJ-2
EC50 (nM)c
K-Ras
EC50 (nM)d
The authors would like to thank K. D. Anderson, P. A.
Ciecko-Steck, A. B. Coddington, G. M. Smith, H. G.
Ramjit, C. W. Ross, III, B.-L. Wan, and M. M. Zrada
for analytical support.
22b
22b
CCFTIa
CCFTIa
0
100
0
1980
1000
2.3
>30,000
1800
>3000
78
100
—
aSee ref 26.
References and Notes
bN-(1-Adamantyl)-4-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)-methyl}-
piperazine-1-carboxamide, compound 1 in ref 14.
cSee ref 24 (assay duration was 24 h).
1. Dinsmore, C. J. Curr. Opin. Oncol. Endocr. Metabol. Invest.
Drugs 2000, 2, 26.
2. Oliff, A. Biochim. Biophys. Acta. 1999, C19, 1423.
3. (a) Hill, B. T.; Perrin, D.; Kruczynski, A. Crit. Rev. Oncol.
Hematol. 2000, 33, 7. (b) Prendergast, G. C. Curr. Opin. Cell
Biol. 2000, 12, 166.
dConcentration of compound required to inhibit prenylation of K-Ras
in PSN-1 cells during a 24 h period by 50% (assay conditions analo-
gous to ref 24).
4. Zhang, F. L.; Kirschmeier, P.; Carr, D.; James, L.; Bond,
R. W.; Wang, L.; Patton, R.; Windsor, W. T.; Syto, R.;
Zhang, R.; Bishop, R. W. J. Biol. Chem. 1997, 272, 10232.
5. Lebowitz, P. F.; Prendergast, G. C. Oncogene 1998, 17, 1439.
6. (a) Zujewski, J.; Horak, I. D.; Bol, C. J. J. G.; Woes-
tenborghs, R.; End, D.; Chiao, J.; Belly, R. T.; Kohler, D.;
Chow, C.; Noone, M.; Hakim, F. T.; Larkin, G.; Gress, R. E.;
Nussenblatt, R. B.; Kremer, A. B.; Cowan, K. H. American
Society of Clinical Oncology 35th Annual Meeting. Atlanta,
GA, 1999. (b) Adjei, A. A.; Erlichman, C.; Davis, J. N.;
Cutler, D. L.; Sloan, J. A.; Marks, R. S.; Hanson, L. J.; Svin-
gen, P. A.; Atherton, P.; Bishop, W. R.; Kirschmeier, P.;
Kaufmann, S. H. Cancer Res. 2000, 60, 1871.
7. Leonard, D. M.; Shuler, K. R.; Poulter, C. J.; Eaton, S. R.;
Sawyer, T. K.; Hodges, J. C.; Su, T.-Z.; Scholten, J. D.;
Gowan, R. C.; Sebolt-Leopold, J. S.; Doherty, A. M. J. Med.
Chem. 1997, 40, 192.
8. Gibbs, B. S.; Zahn, T. J.; Mu, Y.; Sebolt-Leopold, J. S.;
Gibbs, R. A. J. Med. Chem. 1999, 42, 3800.
farnesylation of the FPTase substrate HDJ-223 in PSN-
1
cells with approximately equal potency (EC50
22a=1064 nM, EC50 22b=1332 nM).24
Given the ability of these compounds to inhibit
protein prenylation in cells, an experiment was designed
to investigate the possibility of protein substrate-inde-
pendent inhibition of FPTase by 22b. We chose to
compare inhibition of HDJ-2 processing with that of
K-Ras. Inhibition of K-Ras farnesylation by protein-
competitive inhibitors is generally weaker than inhi-
bition observed for other FPTase substrates due to
the high affinity of FPTase for K-Ras.4 However, an
FPP-competitive inhibitor such as 22b might inhibit
farnesylation of K-Ras and other substrates with equal
potency.
9. (a) Yonemoto, M.; Satoh, T.; Arakawa, H.; Suzuki-Taka-
hashi, I.; Moden, Y.; Kodera, T.; Tanaka, K.; Aoyama, T.;
Iwasawa, Y.; Kamei, T.; Nishimura, S.; Tomimoto, K. Mol.
Pharmacol. 1998, 54, 1. (b) Tahir, S. K.; Gu, W. Z.; Zhang, H. C.;
Leal, J.; Lee, J. Y.; Kovar, P.; Saeed, B.; Cherian, S. P.; Devine,
E.; Cohen, J.; Warner, R.; Wang, Y. C.; Stout, D.; Arendsen,
D. L.; R osenberg, S.; Ng, S. C.Eur. J. Cancer 2000, 36, 1161.
10. For the synthesis and evaluation of related 2-arylindole-3-
acetamides as mDRC ligands and a discussion of the con-
formational properties of these molecules, see: Kozikowski,
A. P.; Ma, D.; Brewer, J.; Sun, S.; Costa, E.; Romeo, E.;
Guidotti, A. J. Med. Chem. 1993, 36, 2908.
11. The anion survey was performed for 22b. The rank order of
anion effects (from lowest observed IC50 to highest) was: dithio-
phosphate (ca. 30-fold reduction in IC50 at 5 mM)<ATP<thio-
sulfate<phosphate<sulfateꢀglycerophosphate (ca. 3-fold
reduction in IC50 at 5 mM).
12. Researchers at Parke-Davis have observed similar effects
in a peptidic series of FPP-competitive FTIs and have pre-
sented evidence that ATP and other anions mimic the phos-
phate group of FPP, thereby enhancing the binding of FPP-
competitive inhibitors that do not otherwise occupy the phos-
phate binding region. See: Scholten, J. D.; Zimmerman, K.;
Oxender, M.; Sebolt-Leopold, J.; Gowan, R.; Leonard, D.;
Hupe, D. J. Bioorg. Med. Chem. 1996, 4, 1537.
13. Graham, S. L.; deSolms, S. J.; Giuliani, E. A.; Kohl, N. E.;
Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Bre-
slin, M. J.; Deana, A. A.; Garsky, V. M.; Scholz, T. H.; Gibbs,
J. B.; Smith, R. L. J. Med. Chem. 1994, 37, 725.
Complicating a direct comparison of HDJ-2 and K-Ras
processing in cell culture is the fact that, while HDJ-2 is
prenylated only by FPTase, K-Ras is a substrate for
both FPTase and GGPTase-I and can therefore be
alternatively geranylgeranylated by GGPTase-I when
FPTase activity is inhibited.25 Thus, 22b alone does
not inhibit processing of K-Ras (EC50 >30,000 nM,
Table 6). However, when geranylgeranylation is
suppressed by addition of a selective GGPTase-I inhi-
bitor (GGTI, GGPTase-I IC50 0.2 nM, FPTase IC50
517 nM),14 22b inhibits K-Ras processing with approxi-
mately the same potency as it does HDJ-2 pro-
cessing (Table 6). In contrast, a Ca1a2X-competitive
FPTase inhibitor (CCFTI, FPTase IC50 0.1 nM,
GGPTase-I IC50 300 nM)26 is 30-fold less potent
against K-Ras than against HDJ-2 under the same
conditions.
In conclusion, FPP-competitive farnesyltransferase
inhibitors which are neither peptidomimetics nor farne-
sylpyrophosphate mimics have been identified. The 2-
arylindole-3-acetamides surveyed here are selective for
FPTase over the related enzyme GGPTase-I and appear
to inhibit protein farnesylation in a protein substrate-
independent manner. As our understanding of the cel-
lular consequences of FPTase inhibition continues to
evolve, this structurally unique class of FTIs may prove
valuable. A more detailed examination of the biological
effects of these compounds awaits the preparation of
analogues with improved cell activity.
14. Huber, H. E.; Abrams, M.; Anthony, N.; Graham, S.;
Hartman, G.; Lobell, R.; Lumma, W.; Nahas, D.; Robinson,
R.; Sisko, J.; Heimbrook, D. C. Proc. Am. Assoc. Cancer Res.
2000, 41, Abstract 2838.

B. W. Trotter et al. / Bioorg. Med. Chem. Lett. 11 (2001) 865–869
869
15. Bishop, W. R.; Bond, R.; Petrin, J.; Wang, L.; Patton, R.;
Doll, R.; Njoroge, G.; Catino, J.; Schwartz, J.; Windson, W.;
Syto, R.; Schwarz, J.; Carr, D.; James, L.; Kirschmeier, P.
J. Biol. Chem. 1995, 270, 30611.
homologation of the acetamide linkage (i–iii, FPTase IC50
>50,000 nM). Conformational restriction of the 2-aryl group
was also deleterious (iv, FPTase IC50 9353 nM).
16. All compounds synthesized in this study exhibited no
measurable inhibition of GGPTase-I (GGPTase-I IC50
>20,000 nM).
17. This nonadditive SARwas further highlighted by obser-
vations in the isobutyl series 10. The 2-pyridyl-methyl analo-
gue 10c (not shown; FPTase IC50 1500 nM) was more potent
than either 10a or 10b, in contrast to the trend seen for other
alkyl substituents (e.g., 7a–c). The possibility exists that a
change in binding mode accompanies the change in amide
substituent size. It is interesting to note that NMRstudies of
representative inhibitors in aqueous solution reveal that both
tertiary amide rotamers are equally populated. Thus, both
rotamers are available for enzyme binding, and the pre-
ferentially bound rotamer may vary with the identities of the
amide substituents.
18. Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron Lett.
1986, 27, 1051.
19. Corresponding para-pyridyl and meta-pyridyl compounds
were prepared; these analogues also exhibited greatly reduced
activity.
23. (a) Adjei, A. A.; Davis, J. N.; Erlichman, C.; Svingen,
P. A.; Kaufmann, S. H. Clin. Cancer Res. 2000, 6, 2318. (b)
Soignet, S.; Yao, S.-L.; Britten, C.; Spriggs, D.; Pezzulli, S.;
McCreery, H.; Mazina, K.; Deutsch, P.; Lee, Y.; Lobell, R.;
Rosen, N.; Rowinsky, E. Proc. Am. Assoc. Cancer Res. 1999,
40, Abstract 3413.
24. EC50=concentration of compound required to inhibit
farnesylation of HDJ-2 in PSN-1 cells during a 7 h period by
50%. Following treatment with 22a or 22b, RIPA lysates of
PSN-1 cells were prepared and analyzed by SDS-PAGE
(25 mg/well) and immunoblotting (anti-HDJ-2, Neomarkers)
to determine extent of prenylation. See ref 23.
25. (a) Rowell, C. A.; Kowalczyk, J. J.; Lewis, M. D.; Garcia,
A. M. J. Biol. Chem. 1997, 272, 14093. (b) Whyte, D. B.;
Kirschmeier, P.; Hockenberry, T. N.; Nunez-Oliva, I.; James,
L.; Catino, J. J.; Bishop, R. B.; Pai, J.-K. J. Biol. Chem. 1997,
272, 14459.
20. Synthesis of these compounds was accomplished by
Fischer indolization of the appropriate ketoamide tolylhy-
drazone precursors (see ref 10). FPTase IC50 values: 7-Me,
702 nM; 5-Me, 8181 nM; 3:1 mixture of 4-Me and 6-Me,
3859 nM.
26. Dinsmore, C. J.; Bogusky, M. J.; Culberson, J. C.; Berg-
man, J. M.; Homnick, C. F.; Zartman, C. B.; Mosser, S. D.;
Schaber, M. D.; Robinson, R.; Koblan, K. S.; Huber, H. E.;
Graham, S. L.; Hartman, G. D.; Huff, J. R.; Williams, T. M.
J. Am. Chem. Soc. 2001, in press.
21. Guida, W. C.; Mathre, D. J. J. Org. Chem. 1980, 45, 3172.
22. In this vein, it is worth noting that a variety of minor
modifications to the 2-arylindole-3-acetamide scaffold were
deleterious to potency. For instance, removal or relocation of
the amide carbonyl obliterated inhibitory activity, as did