Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. the impact of physicochemical properties on ADME and PK

Article abstract of DOI:10.1016/j.bmcl.2010.10.022

HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that

Full text of DOI:10.1016/j.bmcl.2010.10.022

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7429–7434
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II.
The impact of physicochemical properties on ADME and PK
Steven P. Tanis a, , Michael B. Plewe a, , Ted W. Johnson a, Scott L. Butler b, Deepak Dalvie a, Dorothy DeLisle a,
Klaus R. Dress a, Qiyue Hu a, Buwen Huang a, Jon E. Kuehler a, Atsuo Kuki a, Wen Liu a, Qinghai Peng a,
Graham L. Smith a, Jim Solowiej a, Khanh T. Tran a, Hai Wang a, Anle Yang a, Chunfeng Yin a, Xiaoming Yu a,
Junhu Zhang a, Huichun Zhu a
⇑
⇑
a Global Research and Development, Pfizer Inc., 10770 Science Center Drive, San Diego, CA 92121, USA
b Global Research and Development, Pfizer Inc., Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication,
and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the
discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl
hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase
2 glucuronidation pathways. We were able to introduce polar groups at the b-position of the azaindole
core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted
in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative
compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were
accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting oppor-
tunities to alter clearance parameters in future series.
Received 15 September 2010
Revised 2 October 2010
Accepted 5 October 2010
Available online 13 October 2010
Keywords:
HIV integrase
Azaindole hydroxamates
Antiviral
ADME
Ó 2010 Elsevier Ltd. All rights reserved.
PK
Log D
LipE
Physicochemical parameters
Human immunodeficiency virus type 1 (HIV-1), the causative
pathogen of AIDS, replicates utilizing three essential enzymes
encoded in the HIV pol gen: reverse transcriptase (RT), protease
(PR), and integrase (IN). Many anti-HIV agents target either RT1
or PR.2 Recently, inhibitors of IN have emerged as a new promising
class of therapeutics for the treatment of AIDS3,4 highlighted by the
recent approval of raltegravir (1),5,6 and encouraging phase II
clinical trial results with elvitegravir (2)7,8 and S/GSK1349572
(3).9,10 Several drivers remain, however, to discover new chemical
classes with complimentary or improved properties regarding
resistance,11 dosing, and tolerability.
We recently disclosed the discovery of azaindole N-methyl
hydroxamic acids 4 and 5 (Table 1) as potent HIV-1 IN inhibitors.12
Compounds 4 and 5 were stable against oxidative metabolism in
human liver microsomes but were rapidly cleared by phase 2
metabolism via glucuronidation, a well established pathway for
hydroxamic acids.13,14 Here we wish to report our efforts in atten-
uating glucuronidation rates and improving the metabolic stability
O
N
F
O
N
OH O
N
F
HO
Cl
CO2H
OH
F
O
O
N
N
N
N
H
H
H
H
N
N
N
O
O
O
O
O
F
2 elvitegravir
1 raltegravir
3 S/GSK1349572
⇑
Corresponding authors. Tel.: +1 760 918 2482 (S.P.T.); tel.: +1 858 829 8159 (M.B.P).
E-mail addresses: sptanis@sbcglobal.net (S.P. Tanis), mbplewe@gmail.com (M.B. Plewe).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.022

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S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7429–7434
Table 1
Enzymatic and antiviral activity, metabolic stability of b-unsubstituted n-methyl hydroxamic acids
O
OH
N
N
CH3
N
F
X
c Log Da (Log D)
IC50 (nM)
EC50 (nM)
CC50
(lM)
ERd hHEP
LipEe
b
c
c
Compd
4 (X = H)
5 (X = F)
3.06
3.17 (2.40)
250
250
32
39
135
200
1.0
1.0
4.4
4.2
a
b
c
Calculated log D at pH 7.4 using ACD/Physicochem Suite, Version 12 (ACD labs, Toronto, Canada).
Strand transfer scintillation proximity assay (see Supplementary data).
HIV-1 cytopathic effect (CPE) inhibition assay; EC50, 50% effective concentration (see Supplementary data), CC50, 50% cytotoxic concentration (see Supplementary data).
Extraction ratio in human hepatocytes (hHEP) after 4 h incubation; ER = (fu  CLint)/(Q + (fu  CLint)).15
LipE = ÀLog EC50 À c Log D.22
d
e
of substituted variants of the monofluoro azaindole hydroxamate
4. Our focus will be on altering physicochemical parameters (Log P,
Log D, TPSA) through substitution at a more or less potency neutral
locus with the hope of translating this information to future, more
potent, scaffolds.
3-Dimethylaminomethyl azaindole ester 7 was smoothly con-
verted to the related benzylic chloride upon treatment with either
ethyl- or phenyl chloroformate in DCM.19 The benzylic chloride
was coupled with a selection of amines to afford the aminomethyl
azaindoles
9 which were directly converted to the related
Studies of glucuronidation rates with catechols in rat liver con-
cluded that rates are highest for hydrophobic catechols with a pKa
between 8 and 9.16,17 Since the N–OH function (typical pKa be-
tween 8 and 9)18 was critical for activity9 we explored if metabolic
rates could be altered by modifying physical properties, for exam-
ple basicity/acidity/lipophilicity as expressed in a calculated log D
value (c Log D). Fortuitously, the b-position (3-position) in the aza-
indole ring was readily accessible for introduction of a variety of
functional groups covering a range of polarities without substantial
loss in antiviral activity. We explored a variety of different substit-
uents in the b-position and herein we report the impact of these ef-
forts on potencies and metabolic stabilities (determined in human
hepatocytes) of representative examples.
N-methyl hydroxamates 10 when reacted with N-methyl hydrox-
ylamine and sodium methoxide in methanol. In a similar fashion,
dimethylaminomethyl 7 was converted to 3-R1O-methyl substi-
tuted azaindoles 11 (via benzylic chloride and coupling), and these
entities were easily hydrolyzed (aq LiOH) and coupled with N-
methyl hydroxylamine (2-chloro-4,6-dimethoxy-1,3,5-triazine
[CDMT], N-methyl morpholine) to furnish the target 3-CH2OR1-
azaindole hydroxamates 12. Dimethylaminomethyl azaindole
ester 7 was also easily oxidized to the corresponding carboxylic
acid 13 with KMnO4.20 The acid was then coupled with amines
(CDMT) to give amides 14. In turn amides 14 were transformed
into amido-hydroxamates 15 with Na-t-pentoxide and N-meth-
ylhydroxyl amine in NMP.
The b-position of the pyrrolyl ring of the azaindole nucleus is
ideally suited to the facile substitution processes we were seeking
and simple electrophilic substitutions at that position should be
readily achieved. The possibility of ready conversion of the initially
introduced function to a variety of polar substituents made this a
very attractive option to investigate. Scheme 1 illustrates our ini-
tial pyrrolyl b-functionalization chemistry. Azaindole 612 was trea-
ted with N,N-dimethyl(methylene) ammonium chloride (MeCN)19
to provide dimethylaminomethyl-7, while the exposure of 6 to
NIS (DMF, 97%) afforded b-iodo-azaindole 8 (85%). With 7 and 8
in hand we were well positioned for the preparation of a variety
of analogs via conversion of 7 to the related benzylic chloride20
or carboxylic acid,21 while iodide 8 would allow routine palladium
chemistry to be performed.
3-Iodo-azaindole ester 8 was readily coupled with alkynes in a
Sonogashira reaction (PdCl2(PPh3)2, CuI–SMe2, Et3N, DMF) to give
alkynes (Scheme 3) 16 in good (72–98%) yield. Reduction (Pd(OH)2,
H2-40 psi) led to the saturated 3-C extended azaindole esters 17
which were converted to target azaindole hydroxamates 18 when
reacted with N-methyl hydroxylamine in the presence of Na-t-
pentoxide (NMP, 0 °C).
The starting 3-H azaindole hydroxamates 4 and 5 (Table 1)
exhibited reasonable antiviral activity (4 EC50 = 32 nM;
5
EC50 = 39 nM) with poor metabolic stability (ER = 1.0)15 with clear-
ance by phase 2 metabolism via glucuronidation. The clearance
mechanism is expected of hydroxamates and given the relatively
high c Log D values for 4 and 5, 3.06 and 3.17, respectively, rapid
disappearance is not surprising. The combination of reasonable po-
tency and higher than desired c Log D contributes to lipophilic li-
gand efficiency (LipE)22 values of 4.4 and 4.2 for 4 and 5,
respectively. The analogs suggested in Schemes 2 and 3 were de-
signed to alter the physicochemical attributes of the final mole-
cules (c Log D) with an eye toward altering glucuronidation with
a minimal impact upon antiviral activity (EC50). Table 2 presents
the data accumulated for the 3-aminomethyl substituted azaindole
hydroxamates 10a–e.
N
CO2Me
N
N
a
CO2Me
F
7
N
N
I
The compounds of Table 2, 10a–e, are arranged in order of
increasing c Log D (10a c Log D = 0.93 to 10e c Log D = 2.17). While
aminomethyl compounds 10a, 10b, and 10c exhibited disappoint-
ing antiviral activity (EC50’s 150–747 nM) it is of note that the
polarity in the pyrrolyl b-position with the accompanying alter-
ation of c Log D did have the desired impact on the rate of glucu-
ronidation as measured by the ER in human hepatocytes. Of
CO2Me
F
6
b
N
N
F
8
Scheme 1. Pyrrolyl b-functionalization. Reagents and conditions: (a)
dimethyl(methylene) ammonium chloride, DMF, 80 °C, 97%; (b) NIS, DMF, 85%.

S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7429–7434
7431
R1
N
R1
N
O
O
O
R2
R2
CO2Me
OH
N
b
N
N
N
CH3
N
N
F
F
F
F
F
F
9
10
a
R1
O
R1
O
N
CO2Me
CO2Me
OH
c
d
N
N
N
N
N
CH3
N
F
e
7
11
12
R1
N
O
HO2C
R2
CO2Me
X
f
N
N
N
N
13
14 X = OCH3
15 X = N(CH3)OH
g
Scheme 2. The conversion of 3-dimethylaminomethyl azaindole ester 7 to 1-carbon-side chain extended azaindole hydroxamates 10, 12, and 15. Reagents and conditions:
(a) (i) EtOCOCl or PhOCOCl, CH2Cl2, (ii) R1R2NH, i-Pr2NEt, 84–95%; (b) MeNHOH–HCl, NaOMe, MeOH, 29–41%; (c) (i) Ac2O, NaOAc (for R1O = AcO precursor to R1O = HO; or (i)
EtOCOCl or PhOCOCl, CH2Cl2, (ii) R1OH, i-Pr2NEt, 89–97%; (d) (i) aq LiOH, THF, 40 °C, (ii) chloro-dimethoxytriazine, N-methylmorpholine, MeNHOH–HCl, Et3N, DMF, 40–70%;
(e) KMnO4, acetone, H2O, 3 h, 86%; (f) 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methylmorpholine, R1R2NH, i-Pr2NEt, DMF, 22–97%; (g) CH3NOH–HCl, Na-t-pentoxide, NMP,
0 °C, 20–40%.
impact of c Log D. More drastic alterations to the 3-position were
offered by the amides 15a–c.
R1
Table 4 presents our attempts to impart minimal impact upon
I
antiviral activity while altering clearance through the introduction
of amide moieties to the 3-position of the azaindole-hydroxamate
scaffold. This short series of 3 compounds presents a narrow 1 unit
range of c Log D values (1.60–2.64), uniformly disappointing anti-
viral activity (EC50 = 110–210 nM) and uniformly excellent meta-
bolic stability (ER ca. 0.20–0.25).
CO2Me
CO2Me
a
b
N
N
N
N
F
F
8
16
R1
R1
O
N
The final compounds of this study, the Sonogashira derived 3-
carbon-extended 18a–c are depicted in Table 5. As a result of chain
length, c Log D for this short series trends toward that of 4 and 5.
With the exception of the propyl alcohol 18b (EC50 = 41 nM),
poorer antiviral activity was associated with this series than the
3H-compounds 4 and 5. Unfortunately compounds 18a–c also suf-
fered rapid clearance (ER = 0.97–1.0) with the data for 18b
(ER = 1.0) in good agreement with that observed for the 1-car-
bon-alcohol 12a (ER = 1.0) despite a ca. 1 unit difference in c Log D.
An examination of the data presented in Tables 2–5 presents
the amides of Table 4 as curious outliers. Within this small set of
compounds we did not discover a member exhibiting antiviral
activity (EC50) comparable to the R1O-methyl-compounds of Table
3 (12b EC50 = 29 nM, c Log D = 2.19, TPSA = 76.8), or the 3-carbon
extended compounds of Table 5 (18b EC50 = 41 nM, c Log D = 2.66,
TPSA = 76.8). A comparison of the EC50 data as well as c Log D and
TPSA values of 12b and 18b (vide infra) with that of amide 15c
(EC50 = 110 nM, c Log D = 2.64, TPSA = 87.5) suggests we consider
alternatives for the drop-off in antiviral potency. The amides of Ta-
ble 4 provide an electronic pertubation to the system bearing the
metal binding domain and a steric pertubation in the form of
branching proximal to the azaindole ring. The electronic impact
is observed in the calculated pKa for the hydroxamate in the amide
series (c-pKa ca. 7.9) versus the compounds of Table 2 (c-pKa ca.
8.2–8.6), Table 3 (c-pKa ca. 8.1–8.2), and Table 5 (c-pKa ca.
8.1–8.2). A somewhat larger impact is observed when we examine
the pyridine-N of the azaindole system which exhibits an altered
c-pKa for the conjugate acid in the amide compounds of Table 4
(c-pKa ca. 4.5) compared to the compounds of Tables 2, 3, and 5
(c-pKa ca. 5.3–5.7). We might surmise that this electronic
CO2Me
OH
c
N
N
CH3
N
N
F
F
17
18
Scheme 3. The conversion of 3-iodo-azaindole ester 7 to 3-carbon-side chain
extended azaindole hydroxamates 18. Reagents and conditions: (a) PdCl2(PPh3)2,
CuI–SMe2, Et3N, alkyne, DMF, 72–98%; (b) H2 (40 psi), Pd(OH)2, MeOH, 58–95%; (c)
(i) aq LiOH, THF, 40 °C, (ii) 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methylmor-
pholine, MeNHOH–HCl, Et3N, DMF, 45–80%.
greater interest is the concatenation of antiviral activity, similar to
the benchmark compounds 4 and 5, in the proline amide enantio-
meric aminomethyl azaindole hydroxamates 10d (EC50 = 80 nM)
and 10e (EC50 = 94 nM) with stability. In these compounds we have
combined reasonable antiviral activity, a lowering of the c Log D
(by ca. 1 unit), good metabolic stability (ER 6 0.55), and good LipE
values (4.9).
Table 3 presents our attempts to alter the characteristics in this
series by introducing ethereal linkages in the form of 3-R1OCH2-
substituted azaindole hydroxamates 12a–e. With calculated Log D
values ranging from 1.76 (12a) to 2.70 (12e), all the members of
this series have lower c Log D values than the 3H-compounds 4
and 5. Compounds of this series exhibit antiviral activity (29–
57 nM) in the same range as 4 and 5, however diethers 12b
(ER = 0.51) and 12e (ER = 0.57) are much more metabolically stable
than 4 and 5 (ER = 1.0). The unusual pattern with respect to sec-
ondary metabolic clearance shown by this series suggests a possi-
ble role for polarity in the pyrrolyl-b-position over and above the

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S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7429–7434
Table 2
Enzymatic and antiviral activity, cellular cytotoxicity, stability and lipophilic ligand efficiency (LipE) of the acyclic 3-aminomethyl-azaindole N-methyl hydroxamates 10
R1
O
N
R2
OH
N
N
CH3
N
F
10
R1
N
c Log Da (Log D)
TPSA
IC50 (nM)
EC50 (nM)
CC50 (lM)
ERd (hHEP)
LipEe
b
c
c
Compd
R2
HO
10a
10b
0.93
81.8
64.8
1421
534
747
220
>100
>224
0.55
0.55
5.2
5.1
N
N
1.53 (1.80)
N
HN
O
N
10c
10d
10e
1.62
2.17
2.17
90.7
104.7
104.7
388
466
558
150
80
>100
>100
216
0.30
0.50
0.36
5.2
4.9
4.9
CONH2
N
CONH2
N
94
a
b
c
Calculated log D at pH 7.4 using ACD/Physicochem Suite, Version 12 (ACD labs, Toronto, Canada).
Strand transfer scintillation proximity assay (see Supplementary data).
HIV-1 cytopathic effect (CPE) inhibition assay; EC50, 50% effective concentration (see Supplementary data). CC50, 50% cytotoxic concentration (see Supplementary data).
Extraction ratio in human hepatocytes (hHEP) after 4 h incubation; ER = (fu  CLint)/(Q + (fu  CLint)).15
LipE = ÀLog EC50 À c Log D.22
d
e
Table 3
Enzymatic and antiviral activity, cellular cytotoxicity, stability and lipophilic ligand efficiency (LipE) of the acyclic 3-R1O-methyl-azaindole N-methyl hydroxamates 12
R1
O
O
OH
N
N
CH3
N
F
12
R1O
HO
O
b
c
c
Compd
c Log Da (Log D)
TPSA
IC50 (nM)
EC50 (nM)
CC50
(lM)
ERd (hHEP)
LipEe
12a
12b
1.76
78.6
76.8
145
382
54
29
>266
>100
1.0
5.5
5.3
O
2.19 (1.79)
0.51
O
12c
2.35
76.9
313
57
>100
0.86
4.9
O
O
12d
12e
2.52
2.70
67.6
76.8
242
308
41
57
266
81
1.0
4.8
4.5
O
0.57
O
a
b
c
Calculated log D at pH 7.4 using ACD/Physicochem Suite, Version 12 (ACD labs, Toronto, Canada).
Strand transfer scintillation proximity assay (see Supplementary data).
HIV-1 cytopathic effect (CPE) inhibition assay; EC50, 50% effective concentration (see Supplementary data). CC50, 50% cytotoxic concentration (see Supplementary data).
Extraction ratio in human hepatocytes (hHEP) after 4 h incubation; ER = (fu  CLint)/(Q + (fu  CLint)).15
LipE = ÀLog EC50 À c Log D.22
d
e
pertubation has had a negative impact on permeability (not mea-
sured) that is manifest in EC50 values. In addition, one cannot dis-
miss the impact of the amide N–H of 15c on permeability as well.
The aminomethyl compounds of Table 2 are a bit easier to analyze
as the ablation of antiviral activity with increasing c Log D (viz. 10d
EC50 = 80 nM, c Log D = 2.17, TPSA = 104.7: vs 12b/18b) might be
attributed to the permeability impact of increasing TPSA.
After considering the data of Tables 2–5, we selected the 3-ami-
nomethyl compounds 10c, and 10e as representative compounds
for further evaluation in animal species for assessment of their
pharmacokinetic (PK) parameters. Preliminary metabolism studies
suggested that these compounds were readily hydrolyzed to
their corresponding carboxylic acids in rat plasma, possibly by
carboxyesterases. This was consistent with literature reports

S. P. Tanis et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7429–7434
7433
Table 4
Enzymatic and antiviral activity, cellular cytotoxicity, stability and lipophilic ligand efficiency (LipE) of the acyclic 3-carboxamido-azaindole N-methyl hydroxamates 15
R1
O
O
N
R2
OH
N
N
CH3
N
F
15
R1
N
c Log Da (Log D)
1.60 (1.44)
2.21
TPSA
99.3
98.9
IC50 (nM)
503
EC50 (nM)
CC50
(
lM)
ERd (hHEP)
0.25
LipEe
b
c
c
Compd
15a
R2
N
N
HN
210
170
32
5.1
4.5
O
OH
15b
319
>32
<0.20
15c
2.64 (2.36)
87.5
251
110
>100
0.25
4.3
HN
a
b
c
Calculated log D at pH 7.4 using ACD/Physicochem Suite, Version 12 (ACD labs, Toronto, Canada).
Strand transfer scintillation proximity assay (see Supplementary data).
HIV-1 cytopathic effect (CPE) inhibition assay; EC50, 50% effective concentration (see Supplementary data). CC50, 50% cytotoxic concentration (see Supplementary data).
Extraction ratio in human hepatocytes (hHEP) after 4 h incubation; ER = (fu  CLint)/(Q + (fu  CLint)).
LipE = ÀLog EC50 À c Log D.22
d
e
Table 5
Enzymatic and antiviral activity, cellular cytotoxicity, stability and lipophilic ligand efficiency (LipE) of the 3-R1-propyl-azaindole N-methyl hydroxamates 18
R1
O
OH
N
N
CH3
N
F
18
R1
O
b
c
c
Compd
c Log Da
TPSA
IC50 (nM)
EC50 (nM)
CC50 (lM)
ERd (hHEP)
LipEe
18a
18b
18c
2.36
2.66
3.07
70.8
78.6
76.8
559
340
552
470
41
>10
>10
>10
0.98
1.0
4.0
4.7
3.6
N
HO
O
220
0.97
O
a
b
c
Calculated log D at pH 7.4 using ACD/Physicochem Suite, Version 12 (ACD labs, Toronto, Canada).
Strand transfer scintillation proximity assay (see Supplementary data).
HIV-1 cytopathic effect (CPE) inhibition assay; EC50, 50% effective concentration (see Supplementary data). CC50, 50% cytotoxic concentration (see Supplementary data).
Extraction ratio in human hepatocytes (hHEP) after 4 h incubation; ER = (fu  CLint)/(Q + (fu  CLint)).15
LipE = ÀLog EC50 À c Log D.22
d
e
Table 6
which indicated that hydroxamic acids undergo hydrolytic cleav-
age by carboxyesterases in rodent plasma.23,24 Since the selected
compounds were stable in human and dog plasma, further PK
assessment of these compounds were conducted in the dog.
Compound 10c had higher clearance relative to 10e in the dog
(Table 6) while the volume of distribution (Vdss) for these com-
pounds was similar in the dogs and ranged from 1.8 to 2.3. The
moderate to high clearance and moderate volume of distribution
resulted in half-lives of 1.8 h and 6.2 h for 10c and 10e, respec-
tively. Given its more lengthy half life, human PK parameters for
10e were projected using the dog PK data and a single species scal-
ing approach.25 N-Methyl hydroxamate 10e is projected to have
low blood clearance (Clb = 5.5 mL/min/kg), moderate volume of
distribution (Vdss = 2.15 L/kg), moderate bioavailability (F = 41%)
and an estimated half-life in humans of 4.5 h.
Pharmacokinetic profile of compounds 10c and 10e in doga
Clb (mL/min/kg)
Vdss (L/kg)
c
d
Compd
T1/2 (h)
F (%)e
10c
10e
24
15
1.8
2.32
1.27
6.2
20
53
a
b
c
Dose: iv, 1 mg/kg, citrate buffer, pH = 4; po, 5 mg/kg, 5% PEG/methylcellulose.
Plasma clearance.
Volume of distribution.
Half-life.
d
e
Oral bioavailability.
The specificity of 10e for HIV IN was determined by testing
the inhibitor against a variety of human DNA modifying and
metal-dependent enzymes. Compound 10e showed no significant

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inhibition of HCV polymerases, and matrix metalloproteases (IC50
>50 M) and 102 magnesium dependent protein kinases (IC50
>1 M), and is not an inhibitor or a substrate of the 6 major CYP
isoforms (IC50 >30 M for 1A2, 2C8, 2D6, 3A4, 2C9 and 2C19). Com-
pound 10e modestly inhibited hERG potassium channels with an
IC50 of 8.6 M.
Azaindole hydroxamic acids 4 and 5 are HIV Integrase inhibitors
with antiviral cell-based activities comparable to the currently
marketed HIV Integrase inhibitor raltegravir 1 (EC50: 10 nM).5 They
are stable against oxidative metabolism but were rapidly cleared
by glucuronidation. We were able to attenuate clearance rates in
human hepatocytes by introducing polarity at the pyrrolyl-b-posi-
tion of the azaindole hydroxamate nucleus without a dramatic im-
pact upon the antiviral activity of the compounds of interest (viz. 4
and 5 vs 10e and 12b). These observations suggest the utility of a
similar paradigm (substitution to alter clearance) within a series of
intrinsically greater antiviral potency. These activities will be dis-
closed in subsequent reports from these laboratories.
l
l
l
l
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.10.022.
17. Antonio, L.; Grillasca, J.-P.; Taskinen, J.; Elovaara, E.; Burchell, B.; Piet, M.-H.;
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