Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1

Article abstract of DOI:10.1016/j.bmcl.2010.10.079

Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements

Full text of DOI:10.1016/j.bmcl.2010.10.079

Bioorganic & Medicinal Chemistry Letters 21 (2011) 537–541
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide
hydroxyethylamine inhibitors of BACE-1
⇑
Lawrence R. Marcin , Mendi A. Higgins, F. Christopher Zusi, Yunhui Zhang, Michael F. Dee,
Michael F. Parker, Jodi K. Muckelbauer, Daniel M. Camac, Paul E. Morin, Vidhyashankar Ramamurthy,
Andrew J. Tebben, Kimberley A. Lentz, James E. Grace, Jovita A. Marcinkeviciene, Lisa M. Kopcho,
Catherine R. Burton, Donna M. Barten, Jeremy H. Toyn, Jere E. Meredith, Charles F. Albright,
Joanne J. Bronson, John E. Macor, Lorin A. Thompson
Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1
inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme
inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease
selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative
(10n) demonstrated robust reductions in rat plasma Ab levels, but did not lower rat brain Ab due to poor
central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was
likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two
indole HEAs in complex with BACE-1.
Received 19 August 2010
Revised 13 October 2010
Accepted 15 October 2010
Keywords:
BACE
Alzheimer’s disease
Amyloid
Ó 2010 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is an age-related, neurodegenerative
disease afflicting an estimated 5.5 million people in the United
States and more than 35 million people worldwide.1,2 The aberrant
production and/or clearance of b-amyloid (Ab) peptides (predomi-
nately Ab1-42) in the brain has been implicated as the underlying
cause of the disease.3 Increased ratios of Ab1-42/Ab1-40 have been
linked to the formation of neurotoxic Ab oligomers, Ab fibrils, and
plaque-like deposits of aggregated Ab.4 b-Amyloid is produced
through the catabolic metabolism of amyloid precursor protein
(APP) by the sequential action of two enzymes, b-site APP cleaving
analogs with potent in vitro activity.11–13 Unfortunately, poor brain
exposure, attributed to Pgp-mediated efflux at the blood–brain
barrier (BBB), has precluded the central utility of most HEA
BACE-1 inhibitors.7,14–18 Our research program was interested in
exploring heterocyclic replacement of the isophthalamide aryl
ring, and what effect this change would have on BACE-1 binding,
Ab cellular potency, and brain penetration. Specifically, we had
envisioned replacing the aryl ring with a substituted indole.19
Our motive was twofold: (i) indoles are common to many brain-
penetrant pharmaceuticals and (ii) substituted indoles would pro-
vide a unique opportunity to fill the enzyme’s S2 subpocket and
potentially refine BACE-1 potency.
enzyme (BACE-1) and
-secretase decreases the production of Ab peptides and may pro-
vide a disease modifying therapy for the treatment of AD.5 We
have recently detailed our efforts in discovering BMS-708163,6
potent -secretase inhibitor, and are now disclosing studies to-
ward the optimization of BACE-1 inhibitors.7,8
c-secretase. Inhibition of either BACE-1 or
c
Indole-based HEAs 6 were readily prepared as described in
Scheme 1. Indole-3-carboxaldehydes 2 were N-substituted via
a
c
In 2000, crystal structures of BACE-1 in complex with potent
peptidic inhibitors, such as OM99-2,9 provided insight to the ra-
tional design of more drug-like ligands. Two years later, isophthal-
amide hydroxyethylamines (HEAs), such as 1a and 1b, emerged as
transition state mimetics with reduced peptidic character
(Fig. 1).10 Since their initial discovery, numerous reports have
detailed SAR about the isophthalamide aryl ring and disclosed
H
O
H
N
H
N
N
O
O
O
X
1a; X = H
1b; X = F
X
⇑
Corresponding author. Tel.: +1 203 677 6701; fax: +1 203 677 7702.
E-mail address: lawrence.marcin@bms.com (L.R. Marcin).
Figure 1. Known isophthalamide HEA BACE-1 inhibitors.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.079

538
L. R. Marcin et al. / Bioorg. Med. Chem. Lett. 21 (2011) 537–541
R2
R2
R2
three indole-1,3-dicarboxamides 6a–c with N,N-dialkyl substitu-
ents of differing length (Et, n-Pr, and n-Bu) revealed a trend to-
wards greater enzyme inhibition with longer alkyl chain
R3
R3
R3
a
a
b
(BACE-1 IC50 = 1500, 240, 94 nM, respectively). While the enzyme
inhibition of 6b and 6c was similar to that of the analogous isoph-
thalamide 1a, the cellular activity of the indole carboxamides was
significantly inferior. The indole carboxamide and isophthalamide
scaffolds both exhibited a shift toward greater enzyme inhibition
and cellular activity when the P1 phenyl ring had 3,5-difluoro sub-
stitution (Table 1, entries 2 and 6, respectively). However, the cel-
lular potency of the corresponding indole 6d remained poor (Ab
IC50 = 700 nM).
In search of improved cellular potency, we examined a variety
of substituted indoles. The N-(n-butyl)indole 6e was nearly devoid
of BACE-1 inhibitory activity. The N-(n-butylsulfonyl) analog 6f
and the n-butylcarbamate 6g exhibited modest enzyme potency.
The monoalkyl carboxamide 6h (Ab IC50 = 540 nM) exhibited cellu-
lar activity that was comparable to the N,N-dibutyl analog 6d. Im-
proved results were observed for the N-methyl-N-butyl congener
6i (BACE-1 IC50 = 7.4 nM, Ab IC50 = 250 nM). Subsequent SAR ef-
R1
R1
HN
N
N
H
H
O
OH
2
4
O
O
O
3
OH BOC
N
H2N
c, d
+
4
X
5a, X = H
5b, X = F
X
R2
R3
O
OH
H
H
N
R1
N
N
O
X
6
X
Scheme 1. Reagents and conditions: (a) TEA, CH3CN, THF, 60 °C, 24 h with
carbamoylimidazolium methiodide salts;21 or NaH, THF, rt, 2–24 h, with carbamoyl
chlorides and alkyl iodides; or DMAP, ClCH2CH2Cl, rt, 18 h with isocyanates; or
DIEA, CH3CN, 24 h, with alkylsulfonyl chlorides; (b) isobutylene, NaClO2, NaHPO4,
THF, t-BuOH, rt, 24 h; (c) EDC, HOBt, DIEA, DMF, rt, 18 h; (d) TFA, CH2Cl2, rt, 2 h. For
the definitions of R1, R2, R3, and X refer to Table 1.
standard procedures to afford a variety of N-alkyl-, N-alkylsulfo-
nyl-, N-alkyloxycarbonyl-, and N-carboxamidoindoles 3. Sodium
chlorite oxidation of the functionalized carboxaldehydes 3 pro-
vided the requisite carboxylic acids 4. Amide coupling of the car-
boxylic acids 4 with known 1,3-diaminopropan-2-ols 5a,b8,20
provided, after BOC deprotection, the desired final products 6.
Reference compounds 1a,b and novel HEAs 6 were screened for
BACE-1 enzyme inhibition22 and their ability to inhibit secreted
Ab1-40 in cultured HEKsw cells (Table 1).23 An initial survey of
Figure 2. X-ray crystal structures of indole dicarboxamide 6c (depicted in yellow)
and reference isophthalate 1a (depicted in green) in complex with BACE-1. The
BACE-1 flap has been omitted for clarity.
Table 1
BACE-1 binding affinity and cellular Ab potency for compounds 1 and 6
a
a
Entry
Compd
R1
R2
R3
X
BACE-1 IC50 (nM)
HEK-Sw Ab IC50 (nM)
1
2
3
4
5
1a
1b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
—
—
—
—
H
H
H
H
H
H
H
H
H
F
CN
H
H
H
H
H
H
—
—
H
H
H
H
H
H
H
H
H
H
H
F
Cl
H
F
H
H
H
F
H
H
F
F
F
F
F
F
F
F
F
F
F
190
18
1500
240
94
120
31
nd
1300
3200
700
nd
C(O)NEt2
C(O)N(n-Pr)2
C(O)N(n-Bu)2
C(O)N(n-Bu)2
n-Bu
SO2n-Bu
C(O)On-Bu
C(O)N(H)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
C(O)N(Me)n-Bu
6
9
45
38,000
3100
1100
190
7.4
66
120
13
30
18
160
860
70
10
11
12
13
14
15
16
17
18
19
18
19
nd
nd
540
250
420
220
360
820
310
nd
6m
6n
6o
6p
6q
CN
CF3
CO2Bn
CO2H
nd
3000
a
Values are means of P2 experiments (nd = not determined).

L. R. Marcin et al. / Bioorg. Med. Chem. Lett. 21 (2011) 537–541
539
forts focused on holding the N-methyl-N-butylcarboxamide moiety
constant and examining the effect of substitution at the indole
5- and 6-positions. Small electron withdrawing groups at either
position were well tolerated, but a modest preference toward
greater enzyme inhibition was observed for 5-substituted analogs.
The 5-fluoro, 5-chloro, and 5-cyanoindoles (6l, 6m, and 6n, respec-
X-ray crystal structures were determined for two indole HEAs
in complex with full length BACE-1.24,25 The structure of indole
6c and BACE-1 is depicted in Figure 2.26 The graphic is overlayed
with the published crystal structure of isophthalamide 1a.27 As
anticipated, the indole system extends further into the S2 pocket
than the isophthalamide phenyl. Projection of a single carboxam-
ide alkyl chain into the hydrophobic S3 subpocket is similar with
both ligands. For both 1a and 6c, the second alkyl chain forces
the amide carbonyl out-of-plane with respect to the aromatic ring
system and enables hydrogen-bonding of the amide carbonyl with
Thr232. This same alkyl chain is packed against the ligand’s phen-
ylalanyl (Phe) group in the S1 pocket and ultimately creates a con-
tinuous hydrophobic surface that bridges the S1–S3 pockets. While
this intricate S1–S3 binding assembly appears to be maintained
with partially truncated N-butyl-N-methyl analogs (vide infra), it
is likely compromised with the less potent alkyl sulfonamide 6f, al-
kyl carbamate 6g, and secondary carboxamide 6h. Overlay of the
HEA isostere in the catalytic site and the 3-methoxybenzyl group
in the S20 pocket was nearly identical for isophthalamide 1a and in-
dole 6c.
tively) demonstrated potent BACE-1 enzyme activity (IC50
=
13–30 nM), but provided no additional improvement in cellular
potency (IC50 = 310–820 nM).
An X-ray crystal structure of the 5-cyanoindole HEA 6n and
BACE-1 is illustrated in Figure 3.28 The 3,5-difluorophenylalanyl
group (diF Phe) and N-methyl-N-butyl carboxamide have com-
bined to fill the hydrophobic S1–S3 continuous pocket in a highly
efficient manner. Refined stacking interactions of the diF Phe with
Tyr71 of the protein likely contribute to the increased BACE-1
inhibition observed with diF Phe analogs, such as 6i and 6n.
The 5-cyano group of 6n is primary solvent exposed, but may
participate in a
p–cation interaction with Arg235. The cyano
group and Arg235 are separated by approximately 3.1 Å. Efforts
Figure 3. X-ray structure of 5-cyanoindole HEA 6n in complex with BACE-1. The
indole moiety occupies S2 subsite, while the 5-cyano group participates in a
p–cation interaction with Arg235.
N
I
a
N
R1
N
+
HN
H
(57%)
(2 equiv)
O
N
N
N
11
12
O
N
O
O
N
N
7
8
b
R1
O
R1
O
BACE-1 IC50 = 130 nM
Aβ HEKsw IC50 = 130 nM
BACE-1 IC50 = 570 nM
Aβ HEKsw IC50 = 730 nM
N
N
H
OH
(62 %)
O
O
13
14
OH BOC
N
N
H2N
c, d
N
R2
N
N
N
X
O
O
(56 %, 2 steps)
9
10a
15
X
BACE-1 IC50 = 1.3 nM
Aβ HEKsw IC50 = 170 nM
BACE-1 IC50 = 33 nM
Aβ HEKsw IC50 = 89 nM
N
R1
O
OH
H
N
H
N
OH
N
R2
H
N
H
N
O
O
X
O
F
10
X
Scheme 2. Reagents and conditions: (a) TEA, CH3CN, THF, 60 °C, 24 h;21
(b) isobutylene, NaClO2, NaHPO4, THF, t-BuOH, rt, 24 h; (c) EDC, HOBt, DIEA, DMF,
rt, 18 h; (d) TFA, CH2Cl2, rt, 2 h. Yields in parentheses are representative for example
10n. For the definitions of R1, R2, and X refer to Tables 2 and 3.
F
Figure 4. A survey of indole-1,3-dicarboxamide P2 replacements revealed
7-azaindole-1,3-dicarboxamide 10a with good cellular activity.
a

540
L. R. Marcin et al. / Bioorg. Med. Chem. Lett. 21 (2011) 537–541
to further optimize the interaction of Arg235 with indole-5-car-
boxylates, such as 6p and 6q, were unsuccessful (Table 1).
Additional heterocyclic replacements of the isophthalamide
phenyl group are depicted in Figure 4. The pyrrole 7 and pyrroli-
dine 8 analogs displayed modest BACE-1 inhibition (BACE-1
IC50 = 130–570 nM) with little or no shift in cellular potency. The
reversed indole-1,3-dicarboxamide 9 demonstrated excellent en-
zyme potency (BACE-1 IC50 = 1.3 nM), but the functional activity
in cells remained weak.29 The 7-azaindole 10a provided a signifi-
cant breakthrough in Ab cellular potency (Ab IC50 = 89 nM) that
warranted further investigation.
Compound 10a and several related 7-azaindole analogs were
prepared from 1130 by the general route outlined in Scheme 2
(BACE-1 and HEK-Sw Ab data appear in Tables 2 and 3). Conserva-
tive changes in the P20 amine that preserved the meta-substituted
benzyl motif resulted in potent compounds (10b–d), with no clear
advantage over the parent 10a. Ortho substitution of the phenyl
group was not tolerated as exemplified by 10e. Amide,
sulfonamide, and simple alkylamine analogs were all inactive
(10f, 10g, and 10h, respectively).31
Continued studies were focused on a more detailed exploration
of P3 groups for the 7-azaindoledicarboxamide (Table 3). Other
N-methyl-N-alkyl analogs demonstrated good enzyme activity
when one alkyl chain was at least four carbons in length (10i
and 10j). Good to excellent enzyme potency (BACE-1 IC50
=
10–73 nM) was observed for a series of alkyl ether-bearing ana-
logs, 10m–q. The methylprolinol analog 10n32 exhibited the best
enzyme activity (BACE-1 IC50 = 10 nM) and most robust cellular
Ab activity (Ab IC50 = 26 nM) of all the compounds that were
prepared.
The off-target profile33 and c log P34 data for isophthalamide 1b,
indole 6i, 7-azaindoles 10a and 10n are compiled in Table 4. Inter-
estingly, an observation of better cellular potency with decreasing
c log P was evident. This trend may reflect improved cell penetra-
tion with more optimal ligand polarity. While all of the BACE-1
inhibitors exhibited some degree of selectivity against the other
common aspartic proteases, the methylprolinol azaindole 10n
demonstrated superior results. In our assays, it provided improved
selectivity against BACE-2, cathepsin D, cathepsin E, and pepsin
versus the reference isophthalamide 1b.
Table 3
BACE-1 binding affinity and cellular Ab potency for 7-azaindole-1,3-dicarboxamides
10i–q
Table 2
BACE-1 binding affinity and cellular Ab potency for 7-azaindole-1,3-dicarboxamides
10a–h
O
N
N
R1
OH
N
H
N
H
N
N
OH
O
H
N
H
N
N
O
F
R2
X
O
O
F
Compd R1
BACE-1 IC50
(nM)
HEK-Sw Ab IC50
(nM)
a
a
X
a
a
#
R2
X
BACE-1 IC50
(nM)
HEK-Sw Ab IC50
(nM)
10i
10j
N
32
28
79
94
10a
F
33
89
O
N
N
10b
10c
H
F
23
77
Br
10k
10m
10n
210
73
330
110
26
N
8.6
170
O
10d
10e
F
81
360
nd
10
N
O
O
H
6500
10o
10p
12
30
110
160
N
O
10f
H
>100,000
nd
O
O
O
S
N
O
10g
10h
H
H
>100,000
>100,000
nd
nd
O
O
10q
26
170
N
O
a
a
Values are means of P2 experiments.
Values are mean of P2 experiments.

L. R. Marcin et al. / Bioorg. Med. Chem. Lett. 21 (2011) 537–541
541
Table 4
Comparison of BACE-1 enzyme inhibition, cellular Ab activity, and off-target enzyme inhibition for compounds 1b, 6i, 10a, and 10n
a
a
a
Compound
BACE-1 IC50 (nM)
BACE-2 IC50 (nM)
HEK-Sw Ab IC50 (nM)
Cathepsin D IC50 (nM)
Cathepsin E IC50 (nM)
Pepsin IC50 (nM)
c log P
1b
6i
10a
10n
17
16
33
10
230
43
49
31
250
89
2800
170
1900
1500
130
710
380
150
320
4.8
5.9
5.0
4.0
800
26
11,000
4000
1000
a
Values are means of P2 experiments.
16. Iserloh, U.; Pan, J.; Stamford, A. W.; Kennedy, M. E.; Zhang, Q.; Zhang, L.; Parker,
E. M.; McHugh, N. A.; Favreau, L.; Strickland, C.; Voigt, J. Bioorg. Med. Chem. Lett.
2008, 18, 418.
17. Kortum, S. W.; Benson, T. E.; Bienkowski, M. J.; Emmons, T. L.; Prince, D. B.;
Paddock, D. J.; Tomasselli, A. G.; Moon, J. B.; LaBorde, A.; TenBrink, R. E. Bioorg.
Med. Chem. Lett. 2007, 17, 3378.
18. Stanton, M. G.; Stauffer, S. R.; Gregro, A. R.; Steinbeiser, M.; Nantermet, P.;
Sankaranarayanan, S.; Price, E. A.; Wu, G.; Crouthamel, M.-C.; Ellis, J.; Lai, M.-T.;
Espeseth, A. S.; Shi, X.-P.; Jin, L.; Colussi, D.; Pietrak, B.; Huang, Q.; Xu, M.;
Simon, A. J.; Graham, S. L.; Vacca, J. P.; Selnick, H. J. Med. Chem. 2007, 50, 3431.
19. 1-Alkyl-3-carboxamidoindole HEAs, have been disclosed in the patent
literature, but supporting biological data is absent, see: John, V.; Maillard,
M.; Jagodzinska, B.; Beck, J. P.; Gailunas, A.; Fang, L.; Sealy, J.; Tenbrink, R.;
Freskos, J.; Mickelson, J.; Samala, L.; Hom, R. PCT Int. Appl. WO 2003040096.
20. Freskos, J. N.; Fobian, Y. M.; Benson, T. E.; Bienkowski, M. J.; Brown, D. L.;
Emmons, T. L.; Heintz, R.; Laborde, A.; McDonald, J. J.; Mischke, B. V.;
Molyneaux, J. M.; Moon, J. B.; Mullins, P. B.; Prince, D. B.; Paddock, D. J.;
Tomasselli, A. G.; Winterrowd, G. Bioorg. Med. Chem. Lett. 2007, 17, 73.
21. Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R. S.; Batey, R. A.
Tetrahedron 2005, 61, 7153.
Azaindole HEA 10n was examined for its ability to decrease Ab
production in wild type rats. Animals were dosed with a single
intraperitoneal injection of 10n at 30 mpk.35 Plasma and brain sam-
ples were harvested and analyzed for drug exposure and Ab40 lev-
els. Compound 10n demonstrated robust reductions of 51 28%
and 37 16% in plasma Ab at 1.5 and 5 h post injection, respectively.
However, no reduction in brain Ab was observed when the animals
were euthanized at 5 h. The drug achieved robust peripheral expo-
sure ([drug]plasma = 4200 nM @ t = 1.5 h; 2900 nM @ t = 5 h), but
very poor brain exposure ([drug]brain = 57 nM @ t = 5 h). These find-
ings were commensurate with bidirectional Caco-2 permeability
assay results (Papp A–B <15 nm/s; Papp B–A = 184 nm/s), which pre-
dicted a B–A/A–B efflux ratio of >12.36,37 Thus, brain exposure of
10m was likely limited by P-glycoprotein efflux at the blood–brain
barrier.
In conclusion, heterocyclic replacement of the isophthalamide
aryl ring in HEA BACE-1 inhibitors was well tolerated. 7-Azain-
dole-1,3-dicarboxamides with an alkyl ether P3 side chain demon-
strated the best combination of BACE-1 enzyme inhibition and Ab
cellular potency. Azaindole HEA 10n did not achieve sufficient CNS
exposure to effect reductions in brain Ab after a single acute dose.
Exposure data and in vitro permeability studies suggested that the
brain exposure of 10n was probably limited by transporter efflux
at the BBB. Consequently, it does not appear likely that heterocyclic
replacement of the phenyl ring in isophthalamide-derived HEA
BACE-1 inhibitors is a viable strategy to improve CNS exposure
and achieve significant brain Ab reductions.38
22. BACE-1 enzyme activity was determined by the increase in fluorescence
resulting from the cleavage of 7-methoxycoumarin-4-acetyl-EVNLDAEF(K-
dnp)-COOH as described in: Marcinkeviciene, J.; Luo, Y.; Graciani, N. R.; Combs,
A. P.; Copeland, R. A. J. Biol. Chem. 2001, 276, 23790.
23. The cellular HEK-Sw assay was performed as described in Ref. 7.
24. Co-crystals of BACE-1 and a peptidic statine25 were soaked with 1 mM 6c or 6n
in a stabilizing buffer of 35% PEG8 K, 0.2 M ammonium sulfate, 0.1 M sodium
cacodylate pH 6.2 for 25 or 8 days, respectively.
25. Kornacker, M. G.; Copeland, R. A.; Hendrick, J. P.; Lai, Z.; Mapelli, C.; Witmer, M.
R.; Marcinkeviciene, J.; Metzler, W. J.; Lee, V. G.; Riexinger, D. J.; Muckelbauer, J.
K.; Chang, C. J.; Camac, D. M.; Morin, P. E. U.S. Patent Application Publication
2007149763.
26. Coordinates for the complex of BACE-1 with inhibitor 6c have been deposited
in the Protein Data Bank (www.rcsb.org) under PDB ID 3OHF.
27. Patel, S.; Vuillard, L.; Cleasby, A.; Murray, C. W.; Yon, J. J. Mol. Biol. 2004, 343,
407.
28. Coordinates for the complex of BACE-1 with inhibitor 6n have been deposited
in the Protein Data Bank (www.rcsb.org) under PDB ID 3OHH.
References and notes
29. Poor chemical and metabolic stability of
9 cautioned against detailed
interpretation of the assay results and precluded the exploration of
additional analogs belonging to this chemotype.
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