The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs

Article abstract of DOI:10.1016/j.bmcl.2011.01.129

The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the form

Full text of DOI:10.1016/j.bmcl.2011.01.129

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1588–1592
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery of potent and long-acting oral factor Xa inhibitors
with tetrahydroisoquinoline and benzazepine P4 motifs
Nigel S. Watson a, Carl Adams a, David Belton a, David Brown a, Cynthia L. Burns-Kurtis b, Laiq Chaudry a,
Chuen Chan a, Máire A. Convery a, David E. Davies a, Anne M. Exall a, John D. Harling a, Stephanie Irvine a,
Wendy R. Irving a, Savvas Kleanthous a, Iain M. McLay a, Anthony J. Pateman a, Angela N. Patikis a,
Theresa J. Roethke b, Stefan Senger a, Gary J. Stelman b, John R. Toomey b, Robert I. West a,
Caroline Whittaker a, Ping Zhou a, Robert J. Young a,
⇑
a GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom
b GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhib-
itors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues
versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust
candidate for progression towards clinical studies.
Received 17 December 2010
Revised 26 January 2011
Accepted 27 January 2011
Available online 2 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Factor Xa
Oral inhibitors
Property based design
Structure based design
P450 inhibition
The licensing of the first anticoagulants targeting selective
inhibitors of specific enzymes, such as factor Xa (f Xa), in the blood
coagulation cascade has been achieved in a highly competitive and
challenging environment, which has exacting requirements to
achieve potency, selectivity, safety and oral efficacy.1 In the accom-
panying paper,2 the synthesis and evaluation of fXa inhibitors with
the sulfonamidopyrrolidin-2-one template containing the con-
strained indane and phenyl pyrrolidine motifs (Fig. 1; 2A and 2B)
are described, the latter of which delivered a series of candidate
quality molecules that addressed the time-dependant inhibition
characteristics, which were predicted to result in compounds suit-
able for progression as long acting oral anticoagulants.
The requisite 6- and 7-amino 2-N-Boc-THIQ building blocks
were commercially available. 6-amino-5-fluoro-2-N-Boc-THIQ 4
was accessed via 6-amino-5-fluoro isoquinolinone 5, itself
constructed using a modified Bischler–Napieralski procedure from
2-(3,4-difluorophenyl)ethyl amine 6 (Scheme 1). Similarly 2-(4-
fluorophenyl)ethyl amine 7 was converted via 6-nitro-7-fluoro-2-
N- trifluoracetyl-THIQ 8 into the isomeric 7-fluoro intermediate
9. 7-Amino-2-N-Boc-BAZ (10, X = H) was accessed via a literature
route4 from 6-amino tetralone (11, X = H), with modified protect-
ing groups. The same chemistry on 6-amino-5-fluoro-tetralone
(11, X = F), itself constructed from 1-bromo-2,3-difluorobenzene
(12) via Sonogashira coupling, hydrogenation, oxidation and cycli-
sation, furnished 2-N-Boc-7-amino-6-fluoro-2-benzazepine (10,
X = F).
These building blocks were converted into the target com-
pounds, in homochiral form,5 via the established generic route out-
lined in Scheme 2.6 Accordingly, key orthogonally protected
intermediates 13 were prepared by construction of the pyrroli-
din-2-one from Cbz-methionine; ensuing hydrogenolysis followed
by sulfonylation and deprotection furnished the desired test com-
pounds 14.
(TDI) of Cyp3A4 seen in our previously reported
a-methyl benzyl-
amine (
a
MBA) series,3 exemplified by 1. This approach to address
TDI is developed further in this communication through the ra-
tional design, synthesis and evaluation of molecules constrained
by fusion of the benzylic motif into a tetrahydroisoquinoline
(THIQ) ring (2C or 3 m = n = 1). This strategy was extended into
the isomeric 7-THIQ structure (3 m = 2, n = 0) and into the homol-
ogous tetrahydro-2-benzazepine (BAZ) ring system (3 m = 1, n = 2).
Consolidated learnings within the programme gave high confi-
dence that these molecules would display excellent physical
⇑
Corresponding author. Tel.: +44 1438 768372.
E-mail address: Rob.J.Young@gsk.com (R.J. Young).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.129

N. S. Watson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1588–1592
1589
O
O
S
O
S
H
H
N
H
Cl
N
S
R
N
R
O
O
O
O
O
O
N
N
N
X = Y = H,
X = F, Y = H
X = H, Y = F
X
F
X
Y
A
C
N
3
1
2
m( )
( )n
N
H
NHMe
B
Figure 1.
aMBA 1, constraining strategies 2 and generic 6-THIQ (m = 1, n = 1), 7-THIQ (m = 2, n = 0) and BAZ (m = 1, n = 2) 3 structures described.
The evaluation of the 6-THIQ series (15–19) gave very gratifying
results, providing compounds with low nM fXa potency,7 which
translated, as expected, into good levels of anticoagulant activity
(Prothrombin Time, PT assay),8 even with relatively more lipophilic
P1 motifs (Table 1).9 The isomeric 7-substituted series (20–22)
showed generally more modest intrinsic and plasma-based activi-
ties. The potency of the 6-substituted series was rationalised by an
interaction of the protonated distal nitrogen with the backbone
NHCbz
NHSO2R
NH2
Y
X
O
X
O
X
N
N
Y
Y
c,d,e,(f)
a,b
( )n
m( )
N
( )n
m( )
Boc
e.g. 4, 9, 10
( )n
m( )
carbonyl of Glu97 (akin to that seen in the
aVDF series) and
N
N
13
14
H
X-ray structural analysis of 17 bound into fXa supported this ratio-
nale (vide infra); this interaction appeared not to be feasible in the
7-substitued analogues in modelling studies.10
Boc
Scheme 2. Reagents and conditions with representative yields: (a) Cbz-Met-OH,
HATU, DIPEA, DCM, rt, 65–95%; (b) MeI, MeCN, rt, then Cs2CO3, MeCN, 60 °C, 70%;
(c) H2, Pd(OH)2–C, EtOH, rt, quant.; (d) RSO2Cl, pyridine, MeCN, rt, 80–95%; (e) HCl,
MeOH, rt, 95%; (f) for N-TIPS-protected indole-P1; Et4NF, THF, rt 90%.
The rat pharmacokinetic profiles11 for members of the 6-THIQ
series were also very encouraging, showing long half lives but var-
iable oral bioavailability (Table 2); most notably the more
lipophilic 6-chloronaphthyl (6ClNap) analogue 17, possessed a vol-
ume driven extended half-life and acceptable bioavailability. N-
Methyl analogue 15 possessed a much shorter half-life, which is
consistent with findings in related in-house series2,3 for tertiary
versus secondary amino compounds. Disappointingly, poor oral
exposure was achieved with the potent 6-indolyl analogues 18
and 19.
properties, with potential impact on derived PK parameters. These
compounds (Table 3) were found to be essentially equipotent to
the des-fluoro analogues in both activity assays; the PK profiles
were also broadly similar (Table 2), though a trend to lower vol-
umes and lower clearance was apparent. These data also reinforced
observations in the accompanying paper that the 6-indolyl P1
motifs gave attractive intravenous PK profiles, but very poor oral
bioavailability, even if it was at least quantifiable for the fluori-
nated analogues 25 and 28.
Addition of a 5- or 7-fluoro THIQ substituent was designed to
reduce the basicity of the THIQ nitrogen (calculations suggested
that 5-F or 7-F would reduce the pKa by about a log unit, from
the measured value of 9.3 for 16–19), and thus modulate physical
F
F
a,b,c
NH2
F
F
H2N
H2N
d,e
NH
NBoc
NBoc
4
6
5
O
i,j,k
O
O2N
F
f,g,h
NH2
H2N
F
N
F
CF3
9
7
8
X
X
F
H2N
H2N
F
Br l,m,n,o,c
p,b,d,e
NBoc
10
O
12
11
Scheme 1. Reagents and conditions with representative yields: (a) MeOC(@O)Cl, pyridine, DCM, 0 °C, 85%; (b) PPA, P2O5, 120 °C, 20%; (c) NH3, MeOH, 160 °C autoclave, 80%;
(d) BH3, THF,
, 90%; (e) Boc2O, DCM or dioxane, rt, 80%; (f) TFAA, DCM, Et3N, ꢀ5 to 0 °C, 96%; (g) (H2CO)n, concd H2SO4, AcOH, rt, 77%; (h) NaNO3; concd H2SO4, 0 to 5 °C, 45%;
(i) aq HCl, MeOH, , 95; (j) Boc2O, Et3N, dioxane, rt, 76%; (k) H2, Pd–C, EtOH, rt, quant. (l) (Ph3P)2PdCl2, CuI, 3 butyn-1-ol, Me2NH, 65 °C, quant.; (m) H2, 50 psi, Pd(OH)2-C,
EtOH, rt, quant.; (n) pyridinium dichromate, DMF, rt, 65%; (o) MeSO3H, P2O5, rt, 65%; (p) H2NOHꢁHCl, NH4OAc, aq EtOH, 95%.
D
D

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N. S. Watson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1588–1592
Table 1
f Xa inhibitory activities,7 anticoagulant potency8 and physical descriptors9 for compounds 1 and 15–22, with P1 structures and abbreviations
6-THIQ
R1
O
6ClNap
N
Cl
S
R2
N
N
H
O
3S
O
H
N
X = H, 6-Ind
X= Cl, 3ClInd
7-THIQ
X
O
N
S
S
R2
N
Cl
H
O
3S
O
N
H
ClThE
Entry
R2
R1
THIQ
f Xa (Ki, nM)
1.5 ꢂ PT (
l
M)
c log D7.4
MW
cmr
1
6ClNap
ClThE
ClThE
6ClNap
3ClInd
6-Ind
ClThE
6ClNap
3ClInd
—
Me
H
H
H
H
H
H
H
—
2
1
0.6
1
1
nd
8
7.0
3.2
0.9
4.2
1.1
1.3
8.8
12.5
8.4
1.6
1
476
452
438
456
445
411
438
456
445
12.5
11.8
11.4
12.3
11.7
11.2
11.4
12.3
11.7
15
16
17
18
19
20
21
22
6ꢀ
6ꢀ
6ꢀ
6ꢀ
6ꢀ
7ꢀ
7ꢀ
7ꢀ
0.4
0.6
0.4
ꢀ0.5
1.1
1.3
1
10
15
cated 3.0 Å from the backbone carbonyl of Glu97, with two water
molecules mediating hydrogen bonds to the likely protonated
form, with a further relay to Lys96. The distance from the 5-
fluorine to the pyrrolidin-2-one carbonyl carbon was 2.65 Å, con-
sistent with a probable Fꢁ ꢁ ꢁC@O interaction,13 even if it apparently
made no significant contribution towards increasing potency.
Most importantly for this series, no significant TDI of Cyp450
isoforms was observed with 15, 17, 21 and 24;14 thus lending sup-
port to the hypothesis that a putative dihydroisoquinoline metab-
olite might act as a metabolic sink.15 However, in spite of their
highly encouraging profiles the series was discontinued due to rel-
atively potent inhibition of tissue plasminogen activator (tPA), one
of the critical screens in our selectivity panel of trypsin-like serine
proteases (Table 4). It was noted that the N-methyl compound 15
did show much weaker activity against tPA, suggesting that mod-
est changes to the P4 motif could enhance selectivity. A gridding
and partitioning (GAP) analysis of all available tPA data on com-
pounds incorporating P4 variations within the sulfonamidopyrroli-
din-2-one series predicted that the ring expansion from THIQ to
BAZ might reduce tPA activity.
Table 2
Rat DMPK parameters11 for THIQs in Tables 1 and 3
R2
THIQ sub
Clp
a
b
c
Entry
T1/2
(h)
Vss
Fd
(%)
(mL/min/kg)
(L/kg)
1
6ClNap
ClThE
6ClNap
—
H(Me)
H
5F
7F
H
5F
7F
H
1.6
26
18
2.4
0.7
3.6
2.4
1.0
0.9
0.9
0.5
2.9
1.5
0.5
4.1
>10
33
24
nd
28
nd
68
43
<1
7
15
17
24
27
16
23
26
18
25
28
19
0.4
11
4.0
2.1
1.7
3.0
3.0
1.4
7.7
2.7
1.3
12.0
6.7
7.5
3.5
3.3
4.9
6.3
7.8
6.2
6.1
ClThE
3ClInd
6-Ind
5F
7F
H
6
<1
a
b
c
Clp, plasma clearance expressed as mL/min/kg.
T1/2, half-life of the test compound expressed in hours.
Vss, steady state volume of distribution expressed as L/kg.
F, oral bioavailability expressed as percentage.
d
A crystal structure of 24 soaked into f Xa (Fig. 2)12 showed the
predicted binding mode and was almost identical to that estab-
lished for the des-fluoro analogue 17. The THIQ nitrogen atom is lo-
In the BAZ series, excellent levels of potency and anticoagulant
activity were retained, with 6-fluorinated analogues showing a
similar activity profile (Table 5). However, our property based
Table 3
fXa inhibitory activities,7 anticoagulant potency8 and physical descriptors9 for THIQ compounds 16–18 and their fluorinated analogues 23–28
7-F
O
N
S
R2
HN
N
H
O
O
5-F
R2
5-H, 7-H
1.5 ꢂ PT (
5-F, 7-H
5-H, 7-F
1.5 ꢂ PT (
#
f Xa (Ki, nM)
lM)
c log D7.4
#
f Xa (Ki, nM)
1.5 ꢂ PT (
l
M)
c log D7.4
#
f Xa (Ki, nM)
lM)
c log D7.4
ClThE
6ClNap
3ClInd
16
17
18
0.6
1
1
0.9
4.2
1.1
0.4
0.6
0.4
23
24
25
0.6
1.3
2
0.8
4.2
1.7
1.6
1.8
1.5
26
27
28
2
3
1
1.2
7.4
1.3
1.4
1.7
1.4

N. S. Watson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1588–1592
1591
Table 6
Rat DMPK parameters11 for BAZs 29 and 30
a
b
c
Entry
P1
Clp (mL/min/kg)
T1/2 (h)
Vss (L/kg)
F d (%)
29
30
ClThE
6ClNap
7.8
6.8
4.4
9.7
2.6
5.5
45
10
a, b, c, d as Table 2.
In conclusion, the discovery of potent, orally bioavailable, inhib-
itors of blood coagulation factor Xa with long half lives has been
described, rationally addressing Cyp3A4 TDI and unexpected ser-
ine protease selectivity issues. These BAZ inhibitors and the phe-
nylpyrrolidine series described in the accompanying paper2 were
the culmination of an extensive programme driven by structure
and property based design, in which key interactions were
exploited, molecular size/hydrophobicity minimised and aromatic-
ity reduced. The chemical space occupied by the majority of mar-
keted oral drugs can be represented by the median values20
c log P 3.2, c log D7.4 0.8 and MW 420; corresponding values for
29 are c log P 3.2, c log D7.4 1.2, MW 452 and for the equivalent
phenylpyrrolidine2 3.4, 1.1, 470 (respectively). Further data on
the progression of these molecules will be reported in due course.
Figure 2. Overlay of the X-ray crystal structures of 17 and 24 bound into fXa,
showing contacts and water mediated hydrogen bondsin the S4 pocket and the
proximity of the 5-Fꢁ ꢁ ꢁC@O interaction.
Acknowledgements
We gratefully acknowledge the numerous individuals, across
many disciplines, who contributed to the successful discovery
phase of the f Xa programme.
Table 4
Selectivity data versus a panel of trypsin-like serine proteases, expressed as fold
selectivity by ratio of Ki values
Entry
Thrombin
tPA
800
25
8
130
1000
Kallikrein
APC
Plasmin
Trypsin
References and notes
15
16
23
26
29
4000
3200
1300
2500
1000
40
160
20
320
100
>25,000
>25,000
>8000
>25,000
>25,000
10,000
5000
800
800
20,000
>10,000
>25,000
>10,000
>25,000
>25,000
1. (a) Sobieraj-Teague, M.; O’Donnell, M.; Eikelboom, J. Semin. Thromb. Hemost.
2009, 35, 515; (b) Pinto, D. J. P.; Smallheer, J. M.; Cheney, D. L.; Knabb, R. M.;
Wexler, R. R. J. Med. Chem. 2010, 53, 6243.
2. Young, R. J.; Adams, C.; Blows, M.; Brown, D.; Burns-Kurtis, C. L.; Chan, C.;
Chaudry, L.; Convery, M. A.; Davies, D. E.; Exall, A. M.; Foster, G.; Harling, J. D.;
Hortense, E.; Irvine, S.; Irving, W. R.; Jackson, S.; Kleanthous, S.; Pateman, A. J.;
Patikis, A. N.; Roethka, T. J.; Senger, S.; Stelman, G. J.; Toomey, J. R.; West, R. I.;
Whittaker, C.; Zhou, P.; Watson, N. S. Bioorg. Med. Chem. Lett. 2011, 21,
preceding paper.
tPA = tissue plasminogen activator.
APC = activated protein C.
3. Kleanthous, S.; Borthwick, A. D.; Brown, D.; Burns-Kurtis, C. L.; Campbell, M.;
Chan, C.; Chaudry, L.; Clarte, M. O.; Convery, M. A.; Harling, J. D.; Hortense, E.;
Irving, W. R.; Irvine, S.; Pateman, A. J.; Patikis, A. N.; Pinto, I. L.; Pollard, D. R.;
Roethka, T. J.; Senger, S.; Shah, G. P.; Stelman, G. J.; Toomey, J. R.; Watson, N. S.;
West, R. I.; Whittaker, C.; Zhou, P.; Young, R. J. Bioorg. Med. Chem. Lett. 2010, 20,
618.
4. Johnson, P. D.; Aristoff, P. A.; Zurenko, G. E.; Schaadt, R. D.; Yagi, B. H.; Ford, C.
W.; Hamel, J. C.; Stapert, D.; Moerman, J. K. Bioorg. Med. Chem. Lett. 2003, 13,
4197.
5. Compound 15 was produced using the trimethylaluminium methodology
described in Ref. 3, with, by analogy, likely >80% ee. 19F NMR of Mosher amides
of intermediate amines formed by hydrogenolysis of the variations on generic
structure 13 produced using the Methioine route indicated that these
transformations generated homochiral compounds.
6. (a) Harling, J. D.; Watson, N. S.; Young, R. J. WO108709 A1 2006; (b) Camus, L.;
Chudasama, R.; Day, C. J.; Deshmukh, D.; Gleason, J. G.; Harling, J. D.; Lee, C. -P.;
Saklatvala, P.; Senger, S.; Vallance, S.; Watson, J.; Watson, N. S.; Young, R. J.;
Yuan, B. WO 059952 A2 2007.
Table 5
f Xa inhibitory activities,7 anticoagulant potency8 and physical descriptors9 for BAZ
compounds 29–33
O
N
S
HN
R2
N
H
O
X
O
Entry R2
X
fXa (Ki nM) 1.5 ꢂ PT (lM) c log D7.4 MW cmr
29
30
31
32
33
ClThE
H
H
H
F
1
0.9
3.0
1.2
1.1
4.3
1.2
1.4
1
1.9
2.1
452
470
459
470
488
11.8
12.7
12.2
11.9
12.8
6ClNap
3ClInd
ClThE
0.8
0.8
1.3
0.8
6ClNap
F
7. Factor Xa inhibitory activities were determined using Rhodamine 110, bis-
(CBZ-glycylglycyl)-L-arginine amide as the fluorogenic substrate; details are
described in Ref. 19a.
8. Anticoagulant activities were determined in the prothrombin time (PT) assay;
see Ref. 19a, expressed as the concentration required to extend the control
coagulation time by 50% (1.5 ꢂ PT).
design models had suggested that the increased hydrophobicity
and aromatic ring count16 would limit oral bioavailability in com-
bination with the lipophilic 6ClNap P1 motif, which was indeed ob-
served (Table 6). However, the overall potency and DMPK profiles
of (E)-2-(5-chloro-2-thienyl)ethenesulfonamide 29 were strongly
supportive of further progression; allometric scaling was indicative
of once daily dosing in humans,17 whilst appreciable selectivity
was achieved (Table 4) and the risk of Cyp3A4 TDI was effectively
discharged.18 No significant risks with this P1 motif have been
indicated during the continued progression of our first clinical can-
didate GW813893.19
9. Hydrophobicity predictions, expressed as c log D7.4, were all re-calculated using
Advanced Chemistry Development software v11.0 to ensure consistency in this
paper; calculated molecular refractivity (cmr) values were derived from
Daylight software v4.9.
10. Docking studies were undertaken using QXP/FLO, ThistleSoft Inc.: Colebrook, C.
T.; McMartin, C.; Bohacek, R. S. J. Comput. Aided Mol. Des. 1997, 11, 333.
11. Pharmacokinetics measured in male Sprague–Dawley rats following
intravenous and oral administration. The formulation used for both iv and po
dosing was a 5:95% (v/v) mixture of DMSO and 50:50 PEG-200/sterile water.
Serial blood samples were collected into heparinised containers at various
time-points and blood centrifuged to yield plasma. These studies used at least
three animals for each (iv/po) leg.

1592
N. S. Watson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1588–1592
12. The structure for 24 was refined at 1.9 Å (overall Rmerge is 0.049) in Refmac5 to
a final R factor of 0.186 and Rfree of 0.229 using procedures described in Ref.
19a. Co-ordinates are deposited in the protein data bank with code 2y7x.
13. This is consistent with the observation we have previously noted, Young, R. J.;
Borthwick, A. D.; Brown, D.; Burns-Kurtis, C. L.; Campbell, M.; Chan, C.;
Charbaut, M.; Chung, C.-w.; Convery, M. A.; Kelly, H. A.; King, N. P.; Kleanthous,
S.; Mason, A. M.; Pateman, A. J.; Patikis, A. N.; Pinto, I. L.; Pollard, D. R.; Senger,
S.; Shah, G. P.; Toomey, J. R.; Watson, N. S.; Weston, H. E. Bioorg. Med. Chem.
Lett. 2008, 18, 23; An intermolecular C–Fꢁ ꢁ ꢁC@O interaction has been suggested
when fluorine atoms are located within the range of 3–4 Å Olsen, J. A.; Banner,
D. W.; Seiler, P.; Obst Sander, U.; D0Arcy, A.; Stihle, M.; Müller, K.; Diederich, F.
Angew. Chem., Int. Ed. 2003, 42, 2507.
R. J.; Green, D. V. S.; Luscombe, C. N.; Hill, A. P. Drug Discovery Today, 2011
invited submission, manuscript under review.
17. In vitro hepatocyte metabolism data suggested that rat was the best predictor
of likely human disposition; based on the rat PK data reported herein and other
species (to be reported in due course), allometric scaling supported likely once
daily human dosing.
18. Time dependent inhibition (TDI) of 29 versus CYP isoforms was investigated
using the two assays described in the accompanying paper.2 In house, 29 did not
demonstrate TDI of CYP3A4 in the 7BQ assay, over a concentration range of 0.33–
100
was observed in the CYP3A4 DEF assay with approximately twofold shift at
50 M (2.5 times the IC50). In the Biodynamics assay TDI against 3A4 (DEF and
lM. However apparent concentration-dependent TDI of CYP3A4 activity
l
14. Time dependant inhibition of Cyp3A4 was not observed for compounds 15, 17,
21 and 24 in the Biodynamics (www.biodynamics.co.uk) assays described in
the accompanying paper.2
15. (a) Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari, E.; Henne,
K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.; O0Donnell, J. P.; Boer, J.;
Harriman, S. P. Curr. Drug Metab. 2005, 6, 161; (b) Kalgutkar, A. S.; Obach, R. S.;
Maurer, T. S. Curr. Drug Metab. 2007, 8, 407.
16. The recognition of an additive contribution of hydrophobicity plus number of
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