Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.126784

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.

Full text of DOI:10.1016/j.bmcl.2019.126784

Journal Pre-proofs
Heterocycle amide isosteres: an approach to overcoming resistance for HIV-1
Integrase strand transfer inhibitors
Kevin M. Peese, B. Narasimhulu Naidu, Manoj Patel, Chen Li, David R.
Langley, Brian Terry, Tricia Protack, Volodymyr Gali, Zeyu Lin, Himadri K.
Samanta, Ming Zheng, Susan Jenkins, Ira B. Dicker, Mark R. Krystal, Nicholas
A. Meanwell, Michael A. Walker
PII:
S0960-894X(19)30749-8
DOI:
https://doi.org/10.1016/j.bmcl.2019.126784
BMCL 126784
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 September 2019
22 October 2019
24 October 2019
Please cite this article as: Peese, K.M., Narasimhulu Naidu, B., Patel, M., Li, C., Langley, D.R., Terry, B., Protack,
T., Gali, V., Lin, Z., Samanta, H.K., Zheng, M., Jenkins, S., Dicker, I.B., Krystal, M.R., Meanwell, N.A., Walker,
M.A., Heterocycle amide isosteres: an approach to overcoming resistance for HIV-1 Integrase strand transfer
inhibitors, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.126784
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Heterocycle amide isosteres: an approach to overcoming resistance for HIV-1
Integrase strand transfer inhibitors
Kevin M. Peese,* B. Narasimhulu Naidu, Manoj Patel, Chen Li, David R. Langley, Brian Terry, Tricia
Protack, Volodymyr Gali, Zeyu Lin, Himadri K. Samanta, Ming Zheng, Susan Jenkins, Ira B. Dicker, Mark
R. Krystal, Nicholas A. Meanwell and Michael A. Walker.
Departments of Discovery Chemistry and Discovery Infectious Diseases, Bristol-Myers Squibb Research & Development, Wallingford, CT 06492, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and
screened for activity against purified integrase enzyme and/or viruses modified with the
following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations
that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir.
Based on consideration of drug-target interactions, an approach was undertaken to replace the
amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could
retain potency against these key resistance mutations. An imidazole moiety was found to be the
optimal amide substitute and the observed activity was rationalized with the use of calculated
properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds
demonstrated moderate clearance and moderate exposure.
Keywords:
HIV
Integrase inhibitor
HIV Integrase
Strand transfer inhibitor
pyrimidinedione
2014 Elsevier Ltd. All rights reserved.
HIV-1 infection remains a persistent global health problem. In recent years, treatment advances have dramatically improved the
prognosis for HIV-1-infected patients, transforming what was once untreatable into a manageable chronic disease. However, due to
issues associated with resistance and tolerability, there remains a need for new treatment agents.1 HIV-1 integrase, one of three vital
enzymes encoded in the virus genome, is an attractive target for antiviral treatment.2-5 Currently, 1st generation integrase inhibitors
raltegravir, and elvitegravir, and the 2nd generation integrase inhibitors dolutegravir and bictegravir are approved for use in HIV-1-
infected individuals, in combination with other agents (Figure 1).6-9 Despite their success, raltegravir and elvitegravir suffer from
relatively low barriers for the development of resistance mutations.7,8 The ability to be used against viruses resistant to first generation
integrase inhibitors is the goal of 2nd generation HIV-1 integrase inhibitors.*
Incorporation of transcribed viral DNA into the host genome is a critical part of the HIV-1 life cycle and is mediated by the integrase
enzyme.10 HIV-1 integrase catalyzes this process via two separate reactions. The first of these, termed 3’-processing, involves the
cleavage of two base pair nucleotides from the 3’-ends of the reverse transcribed viral DNA. The second catalyzed reaction, termed
strand transfer, involves the insertion of the 3’-processed viral DNA into the host genome. Active site inhibitors act by inhibiting the
strand transfer step and are designated as integrase strand transfer inhibitors (INSTIs).
Figure 1. HIV-1 strand transfer inhibitors.
———
* Corresponding author. Tel.: 203-677-7755; e-mail: kevin.peese@bms.com.

F
O
N
O
O
O
OH
Cl
O
OH
N
H
N
N
F
Me
MeO
Me
OH
O
N
H
Me
Me
Me
Me
N
N
raltegravir
elvitegravir
OH
O
Me
O
OH O
F
F
O
O
F
O
O
N
H
N
H
H
N
N
N
N
O
H
F
F
dolutegravir
bictegravir
Pyrimidinedione amides, including raltegravir and compound 1, bind to the integrase enzyme by coordination of two active site Mg2+
atoms via the “two-metal binding model”.11,12 Once bound in the active site, the compounds do not allow the host DNA to bind. A
primary and robust raltegravir clinical resistance pathway involves mutation of the Q148 residue which confers >25-fold reduction in
potency.13 Mutation at this site affects the affinity of the enzyme for Mg2+ and allows the host DNA to compete better compared to first
generation inhibitors for binding into the active site.14 However, mutations involving the Q148 pathway display impaired replication,
and require a secondary mutation to restore virus growth. For the Q148H mutant, the secondary mutation G140S is necessary to restore
fitness. The reduced Mg2+ affinity of the Q148 mutants suggests a slightly altered coordinating environment surrounding the Mg2+
atoms and, by extension, a structural shift of the position of the Mg2+. Since integrase strand transfer inhibitors chelate two Mg2+ ions in
the active site, such a shift would likely also affect the binding capacity of active site strand transfer inhibitors including the first
generation pyrimidinedione amide 1. To address the proposed altered structure of the binding site of the Q148 mutants, an approach
involving the use of azole heterocycles to replace the amide was initiated within the pyrimidinedione chemotype exemplified by 1. This
change was anticipated to afford a more open geometry that would exhibit greater tolerance of the altered active site of Q148 mutants
(Figure 2). The proximal nitrogen of azole heterocycles would allow for Mg2+ chelation in a similar fashion to the amide oxygen of the
parent amide.11 Optimization of the azole would then be expected to restore activity compromised through the altered geometry of the
metal binding template. This strategy was especially attractive given that resistance coverage of the azole series may be additive with
other orthogonal structural modifications. Our efforts toward implementation of this strategy are detailed herein.
Figure 2. Strategic approach to heterocycles as a metal coordinators.
F
Mg+2
O
Mg+2
O
Mg+2
O
Mg+2
O
O
N
het
modulate geometry
optimize activity
N
H
N
N
N
N
F
Me
Me
Me
Me
1
O
O
F
72o
N
60o
OH
O
OH
O
O
open geometry
N
H
N
N
O
N
N
O
F
Me
Me
Me
Me
1
The use of heterocycles to mimic an amide is well-explored in the literature and has been independently pursued in the context of
HIV-1 integrase inhibitors.15-21 Within a bicyclic pyrimidinedione series, azole amide isosteres were explored in order to optimize wild
type integrase inhibitory activity.16 Further extension of this work demonstrated that thiazoles, in cooperation with other chemical
modifications, were active against raltegravir-resistant mutants.17 In addition to this example, in the context of a hydroxynaphthyridine
series oxadiazoles were established as competent replacements for the amide portion of the metal binding motif.18,19 Another study also
evaluated oxadiazoles as a chemotype for inhibition of the wild-type integrase enzyme.20 The work described herein focused on the
utility of azole isosteres as a strategy specifically to improve activity compared to first generation resistant mutants, while retaining
activity against wild-type integrase.
A series of azole heterocycle derivatives were prepared and evaluated for antiviral activity against NL4-3 virus in a cellular assay
(Table 1). Generally, the majority of heterocycles were tolerated with wild-type potencies within 5-fold of the parent amide (e.g., 2, 3,
5, 6, 8, vs. 1). Exceptions included pyrazole 4, oxadiazole 7, and triazole 9 which all lost substantial activity against the wild-type virus.
Attachment of the benzyl group via N or C had only minor effects on potency against wild type virus, as exemplified by comparing 5
and 6. Establishing potent activity toward the first generation resistance mutations Q148R, G140S/Q148H, and N155H proved to be
more challenging. While most heterocycles offered incremental improvements in potency compared with the parent amide, imidazole
and thiazole replacements provided the most substantial improvement, with the imidazole replacement having the best profile (5 and 6).
Of the resistant mutants evaluated, N155H was consistently the least challenging followed by Q148R, and finally G140S/Q148H.
During this survey, we also evaluated some basic substitution patterns of the heterocycle ring. For example, a methyl group was well
tolerated on the southern position (compare 10 vs. 5 and 11 vs. 9). In contrast, methyl or Cl substitution at the northwest position led to
a complete loss of potency (12 vs. 8, 13 vs. 5). In addition, the regio-connectivity of the benzyl group to the heterocycle was also found
to be critical. The N-methyl imidazole 14 forces the benzyl group to be connected through the northwest position in order to preserve
the metal binding motif of the heterocycle. This substitution pattern, however, resulted in complete loss of activity.

Table 1. Antiviral activity of heterocyclic compounds in a HIV-1 infectivity cellular assay.
F
OH
N
het
O
N
N
Me
Me
O
Compound heterocycle
EC50
(μM)a
EC50
(μM)a
EC50 (μM)a
G140S/Q14
8H
EC50
(μM)a
N155H
CC50
(μM)a
Q148R
O
1
0.003
0.30
>8
0.14
>100
*
*
N
H
N
2
3
4
5
0.022
0.003
0.12
0.33
0.091
3.0
6.9
0.54
4.2
0.088
0.034
0.26
5.3
2.5
7.1
4.4
*
*
*
*
O
S
N
HN
N
N
*
*
*
*
0.006
0.033
0.32
0.002
N
H
N
N
N
6
7
0.004
0.39
0.026
0.19
0.32
>40
0.009
1.3
3.2
99
*
*
*
N
N
*
*
*
N
O
8
9
0.007
0.081
0.22
1.5
3.7
0.016
4.0
18
44
N
N
N
N
>40
*
*
*
*
N
H
10
11
0.010
0.081
0.061
0.45
0.53
1.1
0.036
NA
1.6
35
N
Me
N
N
*
*
*
N
Me
Me
12
13
>30b
>64b
NA
NA
NA
NA
NA
NA
>100
29
N
N
*
N
N
Cl
*
*
N
H
*
14
9.3b
NA
NA
NA
7.0
N
*
N
Me
a) Antiviral activity assayed in an HIV infectivity cellular assay; b) Integrase activity assayed in an in vitro enzyme binding assay.
Our hypothesis suggested that inhibitors with a wider geometry than the parent pyrimidinedione amide series exemplified by 1
would be more capable of binding to the active site of first generation resistant integrases. Indeed, most heterocycles evaluated show a
much improved ratio (EC50 mutant/EC50 wt) against the integrase mutants (Table 2). To better understand the altered potential of the
heterocycle series to chelate Mg2+, we calculated the “bite angle” and partial charge of the Mg2+-coordinating nitrogen. The calculated
values of N-partial charge, with the exception of triazole 8, generally tracked with fold-change compared to the wild type. Imidazoles 5
and 6 showed among the highest partial negative charge on the nitrogen, -0.58 and -0.57, respectively, and the least fold-changes.
Triazole 8 exhibited excellent wild type activity but surprisingly weak activity against the resistant viruses given the high partial charge
on the nitrogen of -0.60. The calculated results concerning the “bite angle” were more ambiguous. The larger bite angle relative to the
parent amide 1 likely does contribute to increased activity against the resistant integrases. However, within the series, subtle differences
in bite angle did not track with resistance activity. The azoles, with the exception of thiazole 3, had a bite angle of 70–74°. Thiazole 3
had a bite angle of 67°, closest to the parent amide 1, and may account for the excellent wild-type inhibitory activity. Imidazoles have
previously been calculated to bind well to Mg2+ in protein environments with an affinity matching or exceeding the corresponding
amide.22 This result agrees well with our findings and provides precedent for the use of imidazole in a Mg2+ chelation capacity.
F

O
N

O
N
N
O
Me
Me

Table 2. Fold resistance vs. wild-type virus and calculated properties of select heterocyclesa
Compound
Q148R
foldb
G140S/Q148H N155H
Bite
angle
(θ)
N partial
foldb
foldb
charge
1
2
3
4
5
6
7
8
9
99
15
30
26
6
>2666
318
177
36
47
4
60.5
70.8
67.4
72.1
71.8
73.4
70.5
72.2
71.7
-0.60 (O)
-0.48
-0.51
-0.54
-0.58
-0.57
-0.40
-0.60
-0.40
11
22
0.3
2
54
7
80
0.5
34
19
>100
563
>500
3
2
49
a) calculated using Schrodinger Maestro Elements; b) EC50 mutant/EC50 wild type.
We also modeled the active sites of the wild-type integrase with amide 1 bound and the G140S/Q148H integrase with imidazole 5
bound based upon the published structure of the closely related prototype foamy virus (PFV) integrase.23,24 The modeling reveals a
distinct structural difference between the binding sites of the wild-type integrase and the G140S/Q148H mutant (Figure 4). The binding
pocket of the wild-type enzyme places the benzyl group of 1 tightly between Q148 and E152. Mutation of glutamine148 to histidine,
however, resulted in a more open pocket that is no longer well occupied by the benzyl amide of 1, a result that was also supported by
recent literature.25 In contrast, the more extended geometry of imidazole 5 is able to occupy much of this increased space thereby
resulting in increased antiviral activity. Overall, the improved resistance coverage of the heterocycle series is likely due to a
combination of the wider geometry of the azoles and its effect on Mg2+ binding coupled with better steric occupation of the mutant
active site. Within the heterocycle series, imidazole is likely the most active due to having the highest partial charge on the azole
nitrogen suggesting optimum Mg2+ binding.
Figure 4. Models of amide 1 bound to wild type integrase and imidazole 5 bound to G140S/Q148H integrase.
S140
Q148
D116
Mg+2
E152
Mg+2
N155
D64
1
Compound bound to PFV integrase (3S3N) wild type

S140
Q148H
E152
D116
Mg+2
Mg+2
D64
N155
5
Imidazole bound to PFV integrase (3S3N) Q148H_G140S
Four heterocycles were advanced into rat IV PK studies (Table 3). Imidazole analogs 5 and 10 were both found to have low
clearance (CL) and very low volume of distribution (Vss), resulting in moderate plasma exposures. In contrast, imidazole 6 and
triazole 8, for which the 4-fluorobenzyl group point of attachment is through a nitrogen atom, were found to have high CL and
moderate Vss, resulting in low exposure.
Table 3. Rat IV PK of lead analogs (1 mg/kg)
Compound
CL (L/min/kg)
Vss (L/kg)
AUC (nM*h)
4550
5
10
6
10
11
0.3
0.5
3.5
1.5
3918
127
52
353
8
872
The series of heterocycles detailed above were readily prepared by published methods from the key starting compounds 15 and 22.26
Oxazole 2 was prepared via amidation of acid 15 with amino ketone 16 and dehydrative cyclization with concomitant debenzylation
(Scheme 1). Thiazole 3 was prepared via an analogous sequence utilizing Lawesson’s reagent-mediated thiodehydrative cyclization
followed by TFA mediated debenzylation. Oxadiazole 7 was also synthesized using an analogous sequence utilizing acyl hydrazide 17
in place of aminoketone 16. Imidazoles 5, 10, 13, and 14 were prepared via published methodology by Zhong et al. (Scheme 2).27
Amide formation from acid 15 with aminonitrile 18, followed by dehydrative chlorocyclization provided chloroimidazole 19. This
pivotal intermediate was subjected alternatively to deprotection, dechlorination/ deprotection, alkylation/deprotection, or
alkylation/dechlorination/deprotection to provide chloroimidazole 13, imidazole 5, methylated chloroimidazoles 20 and 21, and
methylated imidazoles 10 and 14, respectively. Isomeric imidazole 6 was prepared via conversion of acid 22 to methyl ketone 23
followed by bromination, cyclization, benzylation, and deprotection (Scheme 3). Triazoles 8 and 9 were prepared by conversion of acid
15 to thioamide 24 followed by activation, cyclization, and concomitant debenzylation with either acylhydrazide 25 or formylhydrazide
26 to provide triazole 8 and 9, respectively (Scheme 4). Methyltriazole 11 was prepared in a similar sequence by conversion of acid 15
to methylthioamide 27, followed by methylation and cyclization with accompanying debenzylation to give methyltriazole 11 (Scheme
5). Finally, pyrazole 4 was prepared by conversion of acid 15 to diketone 28 followed by hydrazine mediated cyclization and
deprotection to deliver pyrazole 4 (Scheme 6).
F
O
OBn
O
N
OH
HO
a, b, h
O
N
N
O
S
N
N
Me
Me
3
Me
Me
O
15
F
NH2HCl
e, f, g, h
a, d
O
16
F
F
F
Cl
O
N
N
OH
N
OH
17
O
O
O
O
2
7
N
N
N
N
Me
Me
Me
Me
O
O

Scheme 1. Reagents: (a) HATU, DIPEA, DMAP, DMF, DCM; 16; (b) Lawesson's reagent, toluene, heat; (c) H2, 10% Pd/C, MeOH (d) POCl3, toluene, heat; (e)
(COCl)2, DMF, DCM; hydrazine, DCM. (f) 17, TEA, DCM; (g) PPh3, Cl3CCCl3, DIPEA, CH3CN, heat; (h) TFA.
F
F
Cl
O
OBn
Cl
N
OH
OBn
O
N
HO
a, b
O
O
c
N
N
N
N
O
H
H
N
N
N
N
O
F
Me
Me
19
13
Me
Me
Me
Me
O
CN
15
18
NH2HCl
d, c
e
F
F
F
Cl
Cl
Me
N
N
OBn
N
OH
N
OBn
O
O
O
N
N
N
H
+
Me
N
N
O
N
N
N
O
5
20
21
Me
Me
Me
Me
Me
Me
O
d, c
F
F
Me
N
N
OH
N
OH
O
N
O
N
Me
+
N
O
N
N
O
Me
Me
14
10
Me
Me
o
o
Scheme 2. Reagents: (a) (COCl)2, DMF, DCM; 18, DIPEA, DCM; (b) PPh3, CCl4, MeCN, 45 C; (c) LiCl, DMF, 120 C; (d) H2, 10% Pd/C, MeOH (e) NaH,
THF; MeI.
F
OH
N
O
OMe
N
O
OMe
N
N
O
O
O
HO
Me
a, b
c, d, e, f
N
N
N
N
Me
Me
Me
O
Me
O
O
Me
Me
22
23
6
o
o
o
Scheme 3. Reagents: (a) (COCl)2, DMF, DCM; NHMe(OMe)HCl, TEA, DCM; (b) MeMgBr, THF, 0 C; (c) CuBr2, THF, 50 C; (d) formamide, 140 C; (e)
NaH, then 4-F-BnBr, THF; (f) BBr3SMe2, DCE, 80 oC.
OBn
S
24
N
OBn
O
O
O
H2N
a, b ,c
HO
N
N
O
N
N
O
Me
Me
Me
Me
15
d, f
d, e
N
F
F
OH
N
OH
N
O
O
N
N
H
N
N
N
N
O
8
9
Me
Me
Me
Me
O
F
F
O
O
NH2
N
N
NH2
H
25
26
o
o
o
Scheme 4. Reagents: (a) (COCl)2, DMF, DCM; (b) NH4OH, DCM; (c) Lawesson's reagent, THF, 70 C; (d) MeI, MeCN, 50 C; (e) 25, DMF, 140 C; (f) 26,
DMF, 140 oC.
F
N
N
OBn
OBn
OH
O
S
O
Me
O
O
N
HO
N
a, b, c
d, e
H
Me
N
N
O
N
N
O
N
N
Me
Me
15
Me
Me
27
Me
Me
O
11
F
O
NH2
N
H
25

Scheme 5. Reagents: (a) (COCl)2, DMF, DCM; (b) MeNH2, DCM; (c) Lawesson's reagent, THF, 50 oC; (d) MeI, MeCN, 50 oC; (e) 25, DMF, 140 oC.
F
F
HN
OMe
O
O
OH
N
OMe
O
O
O
O
HO
a, b, c
d, e
N
N
O
N
N
N
N
O
Me
Me
Me
Me
15
Me
Me
O
28
4
F
F
f, g
O
O
O
Cl
OtBu
29
30
o
Scheme 6. Reagents: (a) (COCl)2, DMF, DCM; (b) 30, NaH, THF; (c) TFA, 60 C; (d) hydrazine hydrate, EtOH, reflux; (e) BBr3, DCM; (f) Meldrum's acid,
pyridine, DCM; (g) t-BuOH, heat.
Interestingly, a previous study examining the use of azoles in the context of integrase inhibitors found thiazoles to be optimal, a
finding that likely reflects the study’s focus on wild-type activity.16,17 Our work also demonstrates that thiazoles are excellent amide
substitutes in wild-type enzyme inhibitors; however, consideration of resistant mutants indicated that imidazoles exhibit broader
polymorph coverage. Indeed, thiazole was superior to imidazole only for the wild-type. For the three resistance mutations evaluated
(Q148R, G140S/Q148H, and N155H), imidazole was consistently more effective.
In conclusion, we have identified a promising set of heterocycle amide isosteres in the pyrimidinedione series that have increased
capacity for resistance coverage. Against the most resistant mutant G140S/Q148H, coverage was much improved although still not
optimal. However, the heterocycle series may prove useful in combination with other structural modifications to improve resistance
coverage. The best of these compounds, 5 and 10, were both found to have moderate exposure in a rat IV PK screen demonstrating the
viability of this class of structure modification to the parent pyrimidinedione series.
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Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Heterocycle amide isosteres: an approach to
overcoming resistance for HIV Integrase
strand transfer inhibitors
Leave this area blank for abstract info.
Kevin M. Peese,* B. Narasimhulu Naidu, Manoj Patel, Chen Li, David R. Langley, Brian Terry, Tricia Protack,
Volodymyr Gali, Zeyu Lin, Himadri K. Samanta, Ming Zheng, Susan Jenkins, Ira B. Dicker, Mark R. Krystal,
Nicholas A. Meanwell, and Michael A. Walker
F
O
OH
OH
N
5
1
O
O
N
EC50 = 0.006 M
EC50 G140S/Q148H = 0.32 M
N
EC50 = 0.003 M
EC50 G140S/Q148H = >8 M
H
H
N
N
N
N
F
Me
Me
Me
Me
O
O
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential
competing interests:
Graphical Abstract

To create your abstract, type over the instructions in the template box below.
Heterocycle amide isosteres: an approach to
overcoming resistance for HIV Integrase
strand transfer inhibitors
Leave this area blank for abstract info.
Kevin M. Peese,* B. Narasimhulu Naidu, Manoj Patel, Chen Li, David R. Langley, Brian Terry, Tricia Protack,
Volodymyr Gali, Zeyu Lin, Himadri K. Samanta, Ming Zheng, Susan Jenkins, Ira B. Dicker, Mark R. Krystal,
Nicholas A. Meanwell, and Michael A. Walker
F
O
OH
OH
N
5
1
O
O
N
EC50 = 0.006 M
EC50 G140S/Q148H = 0.32 M
N
EC50 = 0.003 M
EC50 G140S/Q148H = >8 M
H
H
N
N
N
N
F
Me
Me
Me
Me
O
O