Naphthyridinone (NTD) integrase inhibitors: N1 Protio and methyl combination substituent effects with C3 amide groups

Article abstract of DOI:10.1016/j.bmcl.2012.11.071

Substituent effects of a series of N1 protio and methyl naphthyridinone HIV-1 integrase strand-transfer inhibitors has been explored. The effects of combinations of the N1 substituent and C3 amide groups was extensively studied to compare enzyme inhibitio

Full text of DOI:10.1016/j.bmcl.2012.11.071

Bioorganic & Medicinal Chemistry Letters 23 (2013) 422–425
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Naphthyridinone (NTD) integrase inhibitors: N1 Protio and methyl
combination substituent effects with C3 amide groups
Brian A. Johns a, , Takashi Kawasuji b, Jason G. Weatherhead a, Eric E. Boros a, James B. Thompson a,
⇑
Cecilia S. Koble a, Edward P. Garvey a, , Scott A. Foster a,à, Jerry L. Jeffrey a, Tamio Fujiwara b
a GlaxoSmithKline Research & Development, Infectious Diseases Therapy Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, USA
b GlaxoSmithKline Research & Development, Infectious Diseases Therapy Area Unit, Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd, 3-1-1, Futaba-cho,
Toyonaka-shi, Osaka 561-0825, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituent effects of a series of N1 protio and methyl naphthyridinone HIV-1 integrase strand-transfer
inhibitors has been explored. The effects of combinations of the N1 substituent and C3 amide groups was
extensively studied to compare enzyme inhibition, antiviral activity and protein binding effects on
potency. The impact of substitution on ligand efficiency was considered and several compounds were
advanced into in vivo pharmacokinetic studies ultimately leading to the clinical candidate GSK364735.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 11 September 2012
Accepted 19 November 2012
Available online 3 December 2012
Keywords:
HIV integrase
GSK364735
Naphthyridinone
Ligand efficiency
HIV therapeutics has been one of the most successful endeavors
in medicine. However as with most infectious diseases, the virus
continues to challenge those therapies which are further compli-
cated by tolerability and adherence problems resulting in subopti-
mal viral suppression over periods of chronic therapy. As a result of
the opposing pressures of drug therapy and viral persistence it
would be remiss for the scientific community to think that HIV is
a solved problem.1 Viral evolution, including the transmission of
resistant virus, is of concern and currently a topic of intense de-
bate.2 Additionally the long term tolerability and safety of many
of the available therapeutic successes are not optimal.3 Of particu-
lar interest are finding regimens that allow delay of the use of
increasingly attractive since the 2007 registration of raltegravir.6
Integrase inhibitors have been well tolerated and are among the
most potent antiretrovirals discovered to date. Raltegravir (RAL)
is a twice daily therapy (400 mg BID) and is saddled with high
PK variability and well established resistance pathways suggesting
that while an excellent drug, there is substantial room for further
study and improvement of the class.7
O
O
OH
F
O
N
O
O
Cl
N
H
OH
N
N
F
O
nucleoside analogs (nuc sparing) until later lines of therapy.4
A
HO
O
N
H
yet more interesting rationale for continued introduction of anti-
retroviral agents ironically comes from the curative approaches
now becoming an area of exploration. It has been argued that
intensification of current regimens will be required for complete
suppression during transcriptional activation envisaged during at-
tempts to purge latent reservoirs.5 As such, there continues to be a
need for new drugs from either new classes or from further study
of existing targets.
N
N
Raltegravir
Elvitegravir
OH
OH
O
O
O
F
F
O
H
N
R3
N
N
H
N
N
O
N
H
O
R1
The inclusion of an HIV-1 integrase inhibitor as part of highly
active antiretroviral therapy (HAART) regimens has become
Dolutegravir
Naphthyridinone (NTD)
⇑
Corresponding author.
E-mail address: brian.a.johns@gsk.com (B.A. Johns).
Current address: Viamet Pharmaceuticals, Inc., Morrisville, NC, USA.
Current address: Chimerix, Inc., Durham, NC, USA.
Two additional integrase inhibitors appear to partially or substan-
tially address the raltegravir limitations. Elvitegravir (EVG) is a once
daily alternative that recently achieved registration in the US but
à
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.071

B. A. Johns et al. / Bioorg. Med. Chem. Lett. 23 (2013) 422–425
423
Table 1
SAR of N1 protio NTD analogs
requires a P450 inhibitor to boost exposures and is highly cross-
resistant to the raltegravir signature mutations.8 Slightly further
behind in development is the carbamoyl pyridone derivative
dolutegravir (DTG) which is a true once daily low dose drug with
no need for PK enhancers and has a superior resistance profile com-
pared to both RAL and EVG.9
OH
O
O
R3
F
N
N
H
N
H
We recently reported the naphthyridinone (NTD) scaffold con-
taining a 7-benzyl moiety to be inhibitors of the HIV integrase
strand transfer step resulting in a potent antiretroviral thus estab-
lishing the core as an attractive platform for further optimization.10
The NTD scaffold consists of the chelating motif that has served to
establish a two-metal binding pharmacophore synonymous with
integrase strand transfer inhibitors.11,12 The emergence of resis-
tance to raltegravir13 suggests a continued need for additional
agents in this class of ARV’s as well as the need for further under-
standings of the scope and limitations of the two-metal binder
class of inhibitor.7 To that end we report herein results of our con-
tinued exploration of structure–activity relationships (SAR) of the
NTD integrase inhibitor series by elaborating on the effects of N1
protio and methyl substitutions (R1) in combination with an array
of C3 amido groups (R3) on biochemical and antiviral activity along
with select pharmacokinetic properties. This work led to the dis-
covery of the clinical candidate GSK364735.14
Compd
R3
(
l
M)
LLE
STIC50
pHIVIC50
pHIVPAIC50
H
5
0.045
0.006
0.005
0.005
0.009
0.009
0.005
0.011
0.066
0.003
0.008
0.005
0.004
0.008
0.006
0.004
0.66
4.8
5.3
3.4
5.2
4.5
3.9
6.1
5.3
CH3
6
0.12
(CH2)2 iPr
(CH2)2 OMe
(CH2)2 OEt
(CH2)3 OiPr
(CH2)2 OH
(CH2)3 OH
7
0.23
8
0.035
0.065
0.19
9
10
11
12
0.051
0.041
During the investigations reported herein, we elected to main-
tain the 7-benzyl moiety consistently substituted with a 4-fluoro
group. It has been shown by us and others that the haloaryl substi-
tution consistently delivers improved potency and may also im-
13
14
0.014
0.023
0.038
0.039
0.172
0.109
3.3
3.7
(CH2)2 N
(CH2)3 N
O
prove pharmacokinetic profiles. Our assay systems involved an
15
integrase biochemical strand transfer assay (STIC50
)
and a single
15
0.004
0.005
0.031
5.4
(CH2)3 N
(CH2)2 N
(CH2)3 N
round pseudotyped antiviral assay utilizing a luciferase reporter
readout (pHIVIC50).16 The pHIV assay also allowed for the addition
of a relevant amount of purified human serum albumin (HSA) to
be used as an estimate of serum protein binding effects on com-
O
16
17
0.007
0.008
0.006
0.006
0.042
0.037
4.8
4.6
pound potency giving rise to a protein adjusted IC50 (
pHIVPAIC50).17
O
All compounds in the series had a substantial therapeutic index
when comparing antiviral potency versus cellular toxicity (data
not shown). An additional measure is included to compare ligand
lipophilicity efficiency (LLE, pIC50-clogP) which is gaining accep-
tance as a key measure of true potency improvement and reduce
toxicity risks.18 In general, it is desirable to have the LLE >5.
The synthetic methods used to prepare the title compounds in
Tables 1–3 began with the substituted 3-amino-2-pyridinecarbox-
ylate ester 1a19 (Scheme 1). This material could be carried forward
directly for the N1 protio analogs or could be methylated using an
intermediate trifluoroacetamide which was alkylated with methyl
iodide and removed with MeOH and potassium carbonate to give
1b. Acylation with the mixed malonate 2 in dichloroethylene with-
out a base resulted in the compounds 3. Dieckmann cyclization to
form the naphthyridinone ring system proceeded smoothly with
sodium ethoxide. At this point, the N1 protio material 4a could
be alkylated to give the N1 methyl intermediate 4b which matched
the material made from the early methylation method using 1b.
Amide formation with a variety of amines was used typically in
neat conditions with heating to give the target drug molecules.
In some cases when the amines were not amenable to use neat,
the condensation was performed in ethanol, DMF or NMP as a
solvent.
NMe
18
19
0.011
0.004
0.028
0.009
0.11
5.3
5.5
(CH2)3 N
(CH2)2 N
0.049
Ms
SO2
20
21
0.009
0.005
0.048
0.005
0.17
6.9
4.6
(CH2)2SMe
0.256
intrinsic potency with the added lipophilicity and molecular
weight. Similar amides in the form of hydroxyalkyl substituents
gave high potency in both the strand transfer and pHIV assays
and also had a very modest protein shift (11–12). The SAR was fur-
ther developed with a representative series of basic amines 13, 14,
16 and 17 and clear improvements in pHIVPAIC50 were observed
with increased polarity of the amine group. LLE values also im-
proved as a result of both clogP decreased and pIC50 increases in
16 and 17 versus 14 and 15. Several sulfur containing analogs were
also examined with sulfone 20 showing the largest LLE. However
this example also demonstrates that, at least for HIV antiretroviral
agents, the situation can be complicated with a significant protein
shift leading to a loss of activity.
From the data set acquired thus far, the most promising analogs
appeared to be alcohols 11 and 12 when LLE and pHIVPAIC50 both
were taken into consideration. As such, a focused set of amino alco-
hols were reacted with 4b to form the corresponding amides
shown in Table 2. Ligand efficiencies are uniformly high with some
differentiation in the HSA-shifted antiviral data. Further substitu-
tion of the hydroxyethyl system did help potency (ꢀ2.5 fold
We initially sought to explore a variety of groups at the C3
amide position while maintaining the ring nitrogen of the naph-
thyridinone system unsubstituted (N1@H). The completely unsub-
stituted primary amide 5 was relatively potent in the biochemical
assay but had a significant loss of potency in the presence of HSA
(Table 1). Increasing the size and lipophilicity of the amide group
had little impact on the enzymatic or antiviral activity but did in-
crease the protein shift. Alkoxyalkyl groups improved pHIVPAIC50’s
(8–10) but at the cost of ligand efficiency with little gain in

424
B. A. Johns et al. / Bioorg. Med. Chem. Lett. 23 (2013) 422–425
Table 2
Table 3
SAR of N1 protio C3 hydroxyalkyl amide NTD analogs
SAR of N1 methyl NTD analogs
OH
O
OH
O
O
R3
R3
F
N
F
N
N
N
H
H
N
H
O
N
CH3
R3
(
l
M)
LLE
5.3
Compd
R3
(
l
M)
LLE
Compd
STIC50
0.005
pHIVIC50
pHIVPAIC50
0.033
STIC50
0.004
pHIVIC50
pHIVPAIC50
0.055
CH3
Et
28
0.001
22
23
24
25
OH
OH
0.007
5.7
5.7
5.5
5.9
29
30
31
32
33
0.004
0.005
0.004
0.008
0.005
0.002
0.001
0.002
0.002
0.001
0.65
4.8
4.7
5.2
5.8
5.5
0.004
0.003
0.003
0.006
0.002
0.007
0.019
0.019
0.078
CF2 H
2.9
(CH2)2 OMe
(CH2)2 OH
(CH2)3 OH
0.048
0.020
0.040
OH
OH
OH
26
27
0.006
0.004
0.007
0.004
0.282
0.041
5.6
4.9
34
35
36
0.008
0.004
0.006
0.002
0.001
0.003
0.011
0.015
0.028
5.3
5.7
5.0
OH
OH
OH
OH
improvement 22–24 vs 11) however again at the expense of ligand
efficiency and thus were not considered significant improvements
in the absence of further data.
37
0.007
0.003
0.18
4.0
OH
OH
Encouraged by the initial NTD SAR, we turned our attention to
improving the scaffold properties. The next logical step was to sub-
stitute at N1 and revisit some of the amide SAR. The unfunctional-
ized amides 28 and 29 performed in a similar manner to the protio
counterparts 6 and 7 whereby potent antiviral activity was ob-
served only to be lost in the presence of HSA. This was further
demonstrated with the difluoroethyl analog 30 resulting in a
2900 fold shift. However, revisiting the methoxy and hydroxyethyl
substitution retained activity with only a modest protein shift with
the alcohol-containing derivative showing an approximately two-
fold improvement in activity over the methyl ether. Further exten-
sion of the chain to a C3 alcohol (33) resulted in a higher protein
shifted value. Slight increases in potency were noticed with the
methyl substituted amide chains in 34 and 35 however at the cost
of slightly lowered LLE due to increased lipophilicity. Increased
branching of the hydroxyethyl chain substitution SAR did not show
improvements in either LLE or pHIVPAIC50 measures (36–38). How-
ever, improvements in LLE as a result of a lowered clogP were ob-
served for diol enantiomers 39 and 40 through translation into
greater antiviral activity was not observed. Basic amine containing
tails 41 and 43 while potent did not deliver any improvements in
activity and suffered some loss of LLE. Similarly, the pyrrolidione
analog 42 had excellent potency as a result of an attenuated pro-
tein shift value. The addition of a nitrogen to give urea 44 provided
a slight improvement in potency along with LLE. Similar potency
levels were attained with the acetamide 45 and N-methyl-N-meth-
ylsulfonamide 46.
38
39
40
41
0.002
0.003
0.004
0.006
0.002
0.002
0.003
0.009
0.11
5.6
6.1
6.1
3.9
OH
OH
0.015
0.018
0.034
OH
OH
(CH2)3 N
O
42
43
44
0.016
0.013
0.005
0.002
0.004
0.002
0.015
0.023
0.009
4.6
4.4
5.8
(CH2)3 N
O
(CH2)2 N
O
NH
(CH2)2 N
(CH2)2 NHAc
45
46
0.005
0.005
0.002
0.001
0.012
0.007
5.8
5.4
(CH2)2 N
Ms
derivative. The urea, acetamide and sulfonamide analogs 44, 45, 46
that were highly potent in the pHIV assay fell off slightly in activity
in the MT4 system.
A select group of compounds from the protio and methyl series
were assayed in an MT4 cell multicycle full replication assay (Table
4). Some differences in activity were observed such as comparing
compound 11 and 32 which differ only in the N1 protio versus
methyl substituent respectively. The methyl analog 32 is threefold
more potent in the pseudotyped assay but over 16-fold better in
the MT4 assay. The related analog pairing of 22 and 34 whereby
a methyl branch is added to the amide group results in a fivefold
differential favoring the N1 methyl analog 34. Conversely, the more
polar basic amine pair 16 and 43 while both less potent, have an
only twofold activity difference favoring in this case the N1 protio
The pharmacokinetic (PK) properties of the two sets of analogs
were evaluated using male CD rats as a screening species. Initially
select compounds from those with the highest potency were
examined using oral dosing with AUC(0–24 h) and the ratio of
the concentration at 24 h divided by the PAEC50 as key measures
to decide on further progression. Three compounds in Table 5
showed significantly elevated oral AUC levels (32, 35, and 39).
Based on the rat data, the three best compounds based on oral
AUC’s were taken into a dog study (Table 6). Unfortunately, the
methyl substituted hydroxyethyl amide 35 and diol 39 had only
modest exposure from oral dosing. However, the hydroxylethyl

B. A. Johns et al. / Bioorg. Med. Chem. Lett. 23 (2013) 422–425
425
O
O
high oral bioavailability (97%F). This combined with a highly po-
tent protein adjusted EC50 justified further progression of 32 into
safety assessment evaluation and ultimately it was chosen for clin-
ical evaluation. Compound 32 is also known as GSK364735.14,20,21
OMe
O
O
N
N
Cl
OEt
e
2
OMe
R1
N
O
NH
R1
d
O
OEt
References and notes
1a R1 = -H
3a R1 = -H
a,b,c
1b R1 = -CH3
3b
R
1 = -CH3
1. Fauci, A. S.; Morens, D. M. New Engl. J. Med. 2012, 366, 454.
2. (a) Truong, H.-H. M.; Kellogg, T. A.; McFarland, W.; Louie, B.; Klausner, J. D.;
Philip, S. S.; Grant, R. M. Plos One 2011, 6, 1; (b) Wittkop, L.; Günthard, H. F.;
Dunn, D.; Cossi-Lepri, A.; de Luca, A.; Kücherer, C.; Obel, N.; von Wyl, V.;
Masquelier, B.; Stephan, C.; Torti, C.; Antinori, A.; Garcia, F.; Judd, A.; Porter, K.;
Thiébaut, R.; Castro, H.; van Sighem, A.; Colin, C.; Kjaer, J.; Lundgren, J. D.;
Paredes, R.; Pozniak, A.; Clotet, B.; Philips, A.; Pillay, D.; Chêne, G. Lancet Infect.
Dis. 2011, 11, 363; (c) Jain, V.; Liegler, T.; Vittinghoff, E.; Hartogensis, W.;
Bacchetti, P.; Poole, L.; Loeb, L.; Pilcher, C. D.; Grant, R. M.; Deeks, S. G.; Hecht, F.
M. Plos One 2010, 5, 1.
F
F
OH
O
O
OH
O
N
g
N
R3
OEt
N
H
N
N
O
R1
R1
4b R1 = -CH3
5-46
f
4a
3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Dept. of Health
and Human Services. October 2011. <http://aidsinfo.nih.gov/contentfiles/
adultandadolescentGL.pdf>.
R
1 = -H
F
F
4. (a) Taiwo, B.; Zheng, L.; Gallien, S.; Matining, R. M.; Kuritzkes, D. R.; Wilson, C.
C.; Berzins, B. I.; Acosta, E. P.; Bastow, B.; Kim, P. S.; Eron, J. J., Jr. AIDS 2011, 25,
2113; (b) Reynes, J.; Lawal, A.; Pulido, F.; Soto-Malave, R.; Gathe, J.; Tian, M.;
Frerick, L. M.; Podsadecki, T. J.; Nilius, A. M. HIV Clin. Trials 2011, 12, 255.
5. Perelson, A. S.; Deeks, S. G. Sci. Transl. Med. 2011, 3, 91ps30.
6. (a) Thompson, M. A.; Adberg, J. A.; Cahn, P.; Montaner, J. S. G.; Rizzardini, G.;
Telenti, A.; Gatell, J. M.; Günthard, H. F.; Hammer, S. M.; Hirsch, M. S.; Jacobsen,
D. M.; Reiss, P.; Richman, D. D.; Volberding, P. A.; Yeni, P.; Schooley, R. T. JAMA
2010, 304, 321; (b) Zolopa, A. Antiviral Res. 2010, 85, 241.
Scheme 1. Reagents and conditions: (a) TFAA, DCE; (b) MeI, CH3CN, K2CO3,
(c) K2CO3, MeOH; (d) DCE, ; (e) NaOEt, EtOH; (f) LiHMDS, MeI, DMF; (g) amine
(neat),
D;
D
D
.
Table 4
MT4 antiviral activity
Compd
MT4IC50
(lM)
T.I.22
7. Pendri, A.; Meanwell, N. A.; Peese, K. M.; Walker, M. A. Expert Opin. Ther. Patents
2011, 21, 1173.
11
16
22
32
34
43
44
45
46
0.080
0.032
0.020
0.005
0.004
0.064
0.011
0.022
0.007
>250
>250
>400
>2000
>12,500
165
1616
807
>7200
8. (a) Sato, M.; Kawakami, H.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita,
M.; Ito, Y.; Matsuzaki, Y.; Yamataka, K.; Ikeda, S.; Shinkai, H. J. Med. Chem. 2009,
52, 4869; (b) Willis, T.; Vega, V. Expert Opin. Investig. Drugs 2012, 21, 395;
Desimmie, B. A.; Schrijvers, R. Q.; Debyser, Z. Lancet Infect. Dis. 2012, 12, 3.
9. Kobayashi, M.; Yoshinaga, T.; Seki, T.; Wakasa-Morimoto, C.; Brown, K. W.;
Ferris, R.; Foster, S. A.; Hazen, R. J.; Miki, S.; Suyama-Kagitani, A.; Kawauchi-
Miki, S.; Taishi, T.; Kawasuji, T.; Johns, B. A.; Underwood, M. R.; Garvey, E. P.;
Sato, A.; Fujiwara, T. Antimicrob. Agents Chemother. 2011, 55, 813.
10. Boros, E. E.; Edwards, C. E.; Foster, S. A.; Fuji, M.; Fujiwara, T.; Garvey, E. P.;
Golden, P. L.; Hazen, R. J.; Jeffrey, J. L.; Johns, B. A.; Kawasuji, T.; Kiyama, R.;
Koble, C. S.; Kurose, N.; Miller, W. H.; Mote, A. L.; Murai, H.; Sato, A.; Thompson,
J. B.; Woodward, M. C.; Yoshinaga, T. J. Med. Chem. 2009, 52, 2754.
11. Kawasuji, T.; Fuji, M.; Yoshinaga, T.; Sato, A.; Fujiwara, T.; Kiyama, R. Bioorg.
Med. Chem. 2006, 14, 8420.
Table 5
Rat in vivo pharmacokinetic screening results23
12. Kawasuji, T.; Yoshinaga, T.; Sato, A.; Yodo, M.; Fujiwara, T.; Kiyama, R. Bioorg.
Med. Chem. 2006, 14, 8430.
Compd
Clp (mL/min/kg)
T1/2 (h)
po AUC (ng h/mL)
C24/pHIVPAIC50
13. Wainberg, M. A.; Zaharatos, G. J.; Brenner, B. G. New Engl. J. Med. 2011, 365, 637.
14. Garvey, E. P.; Johns, B. A.; Gartland, M. J.; Foster, S. A.; Miller, W. H.; Ferris, R. G.;
Hazen, R. J.; Underwood, M. R.; Boros, E. E.; Thompson, J. B.; Weatherhead, J. G.;
Koble, C. K.; Allen, S. H.; Schaller, L. T.; Sherrill, R. G.; Yoshinaga, T.; Kobayashi,
M.; Wakasa-Morimoto, C.; Miki, S.; Nakahara, K.; Noshi, T.; Sato, A.; Fujiwara, T.
Antimicrob. Agents Chemother. 2008, 52, 901.
8
ND
ND
ND
11.8
3.2
ND
ND
ND
ND
ND
ND
ND
4.0
1.5
ND
ND
ND
ND
1649
3060
6374
1850
22,806
22,552
12,570
3548
0.1
0.8
0.0
0.1
0.3
2.7
1.8
0.0
1.7
11
22
31
32
35
39
44
46
15. Recombinant HIV-1 integrase strand transfer assay. Boros, E. E.; Johns, B. A.;
Garvey, E. P.; Koble, C. S.; Miller, W. H. Bioorg. Med. Chem. Lett. 2006, 16, 5668.
16. Pseudo-type HIV assay (PHIV). Garvey, E. P.; Johns, B. A.; Gartland, M. J.; Foster,
S. A.; Miller, W. H.; Ferris, R. G.; Hazen, R. J.; Underwood, M. R.; Boros, E. E.;
Thompson, J. B.; Weatherhead, J. G.; Koble, C. S.; Allen, S. H.; Schaller, L. T.;
Sherrill, R. G.; Yoshinaga, T.; Kobayashi, M.; Wakasa-Morimoto, C.; Miki, S.;
Nakahara, K.; Noshi, T.; Sato, A.; Fujiwara, T. Antimicrob. Agents Chemother.
2008, 52, 901.
5813
17. pHIVPAIC50 is determined using 40 mg/mL of purified human serum albumin in
the pHIV assay
18. Leeson, P. D.; Empfield, J. R. Annu. Rep. Med. Chem. 2010, 45, 393.
19. Boros, E. E.; Burova, S. A.; Erickson, G. A.; Johns, B. A.; Koble, C. S.; Kurose, N.;
Sharp, M. J.; Tabet, E. A.; Thompson, J. B.; Toczko, M. A. Org. Process Res. Dev.
2007, 11, 899.
Table 6
Dog and cynomolgus monkey in vivo pharmacokinetic data23
Compd Species Clp (mL/min/kg) T1/2 (h) po AUC
C24/pHIVPAIC50
(ng h/mL)
20. Therapeutic index (cytotoxicity IC50/EC50).
28
28
31
35
Dog
Cyno
Dog
Dog
8.6
2.0
ND
ND
1.6
3.9
ND
ND
13,230
38,600
1241
0.8
9.2
0.0
0.0
21. Nakahara, K.; Wakasa-Morimoto, C.; Kobayashi, M.; Miki, S.; Noshi, T.; Seki, T.;
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1123
22. Kobayashi, M.; Nakahara, K.; Seki, T.; Miki, S.; Kawauchi, S.; Suyama, A.;
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amide 32 again had a robust AUC exposure with evidence for drug
levels at 24 h after dosing. Compound 32 was then progressed into
a cynomolgus monkey low dose iv/po pk study and showed excel-
lent exposures. The compound demonstrated low clearance and
23. Oral doses of 5 mg/kg were delivered as
a
DMSO/solutol/water solution
formulation. IV data was from
performed in fasted animals.
a 1 mg/kg bolus injection. Studies were