Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles

Article abstract of DOI:10.1021/acsmedchemlett.7b00170

A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of 24, a highly potent and selective inhibitor of PI3Kδ.

Full text of DOI:10.1021/acsmedchemlett.7b00170

Subscriber access provided by JAMES COOK UNIVERSITY LIBRARY
Letter
Design of Selective Benzoxazepin PI3K#
Inhibitors Through Control of Dihedral Angles
Brian Salvatore Safina, Richard L Elliott, Andrew K. Forrest, Robert A. Heald, Jeremy
M. Murray, Jim Nonomiya, Jodie Pang, Laurent Salphati, Eileen M Seward, Steven
Thomas Staben, Mark Ultsch, Binqing Wei, Wenqian Yang, and Daniel P. Sutherlin
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00170 • Publication Date (Web): 25 Aug 2017
Downloaded from http://pubs.acs.org on August 26, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
Design of Selective Benzoxazepin PI3Kδ Inhibitors Through
Control of Dihedral Angles
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Brian S. Safina, † Richard L. Elliott§, Andrew K. Forrest§, Robert A. Heald§, Jeremy M. Murray†, Jim
*
Nonomiya†, Jodie Pang†, Laurent Salphati†, Eileen M. Seward§, Steven T. Staben†, Mark Ultsch†,
Binqing Wei†, Wenqian Yang‡ and Daniel P. Sutherlin†
†Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 ‡ChemPartner, 998 Halei Road,
Zhangjiang Hiꢀtech Park, Pudong New Area, Shanghai China, 201203 §Discovery from Charles River, 8ꢀ9 Spire Green
Centre, Harlow, Essex, CM 19 5TR, United Kingdom
KEYWORDS: PI3K delta inhibitor, PI3K isoform selectivity, ligand-based design
ABSTRACT: A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K
inhibitor we utilized structureꢀbased drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ
isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of 24, a
highly potent and selective inhibitor of PI3Kδ.
A key tenet in ligandꢀbased drug design is
optimization of ligand conformation. The preferred
low energy conformation of a ligand bound to its
receptor results in a lower free energy of the
complex.1 While covalentlyꢀlinked ring systems
effectively control threeꢀdimensional shape, single
rotatable bonds rely on more subtle nonꢀcovalent
interactions to control conformation, often having
the added advantage of minimal synthetic
complexity and improved drugꢀlike properties.2,3
An understanding of the stereoelectronic and steric
effects governing torsion angles of single rotatable
bonds allows for maximum control of ligand
conformation. Low energy torsion angles can be
computationally derived and combined with data
Figure 1. a) PI3Kδ potent and selective inhibitors 1
(GNEꢀ293) and 2 derived from morpholine pyrimidine
core. b) Crystal structure of compound 2 (purple)
bound to PI3Kδ; PDB 4GB9.
from the Cambridge Structural Database (CSD) to
aid in design.4,5,6 Combining these tactics with
Phosphoinositideꢀ3ꢀkinase delta (PI3Kδ) is a lipid
kinase that has been implicated to play a key role in
a variety of immuneꢀmediated disorders such as
structureꢀbased drug design provides a powerful
tool for optimization.
asthma,
rheumatoid
arthritis
and
other
O
O
N
a)
inflammatory disease.7 Isoform selectivity is
critical to study the function of the PI3K pathway
and to maximize the therapeutic indices.8 We
previously disclosed potent and selective inhibitors
of PI3Kδ 1 (GNEꢀ293) and 2 (Figure 1a), derived
from a morpholine pyrimidine core. Compounds 1
and 2 are resultant from work to optimize potency
and isoform selectivity via targeting specific
proteinꢀligand interactions in an affinity pocket and
a “tryptophan shelf”.9,10,11 In an effort to further
expand the structural diversity of our selective
PI3Kδ inhibitors we sought to capitalize on an
alternative scaffold derived from our benzoxazepin
class of PI3K inhibitors, exemplified by αꢀselective
compound 3 (GDCꢀ0326, Figure 2a).12
N
N
N
N
N
N
N
O
N
N
N
N
N
N
N
N
N
S
HO
O
2
1 (GNE-293)
O
Kiapp (nM)
Kiapp (nM)
PI3K
PI3K
α
β
α
β
360
1566
6
556
120
197
0.47
103
δ
δ
γ
γ
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 2 of 6
1
2
3
4
5
6
a)
O
O
N
8
O
H2N
9
N
N
7
8
9
N
N
3: GDC-0326
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Kiapp (nM)
PI3K
α
β
0.2
22.5
4.5
14.8
δ
γ
Figure 3. Dihedral angle histogram from the The
Figure 2. a) Compound
3 (GDCꢀ0326) αPI3K
Cambridge Structural Database (Mogul CSD v5.37)
for a) methylene linker, b) amide linker, c)
sulfonamide linker and d) sulfoxide linker.
isoform inhibitor derived from the benzoxazepin core.
b) Crystal structure of compound 3 (green) bound to
PI3Kα (cyan); PDB 5DXT.
Accordingly, four functional groups with a range of
rotameric preferences were computationally
analyzed (methylene, amide, sulfonamide and
sulfoxide) to identify a preferred rotamer capable of
extending from the C9ꢀaryl benzoxazepin position
to maximize interactions with Trp760.9 A statistical
analysis of the torsion angles for each generic
functional group from the CSD is depicted in
Figure 3aꢀd and the results were used as a selection
criteria. Each histogram represents the observed
Our strategy to optimize the benzoxazepin scaffold
(3) towards a PI3Kδꢀselective inhibitor was very
attractive for several reasons.
Firstly, the
benzoxazepin scaffold was the result of extensive
ADME optimization and thus already possessed
favorable drug like properties.13,14 Secondly, 3 was
already potent against PI3Kδ making isoform
selectivity the starting challenge.
Lastly,
comparison of coꢀcrystal structures from the
morpholine pyrimidine class 2 and benzoxazepin
class 3 (Figure 1b and 2b) revealed an opportunity
to access a tryptophan shelf (Trp760 in PI3Kδ).
This strategy had been successful for driving
isoform selectivity in the optimization of the
morpholine pyrimidine series where our structural
rationale for PI3Kδ selectivity depended on forging
favorable interactions with Trp760, which in PI3Kδ
formed the base of a relatively large pocket (2
bound in PI3Kδ, Figure 1b). 9 In PI3Kα this pocket
is occluded by an arginine residue (Arg770) as
depicted in Figure 2b with the coꢀcrystal structure
of GDCꢀ0326 in PI3Kα.12 Our strategy was to
incorporate functional groups capable of interacting
with Trp760 (δ) and thereby simultaneously forge
offensive interactions with PI3Kα (as well as β and
γ) where large residues occlude a “tryptophan
shelf”.9 Further analysis of the crystal structure
suggested that the best vector to interact with the
Trp shelf to increase selectivity was from the C9ꢀ
aryl position of the benzoxazepin core (Fig 2b).
frequency of torsion angles (0° to 180°) for a
particular functional group.
In addition to
identifying the preferred rotamer from the observed
frequency (number of hits), one can also infer
relative energy differences between rotamers. For
example, (Figure 3a) a CSD search of fragments
containing a benzyl amine moiety, not surprisingly
shows
a relatively flat histogram and weak
rotameric preference, implying low rotational
barriers and fewer restrictive conformations.
Substitution of the methylene with a carbonyl to
yield an amide moiety produced a histogram with
sharp peaks at 45° (and 135°) implying higher
rotational barriers and consequently,
a more
restrictive conformation (Figure 3b). In contrast, a
sulfonamide moiety predominantly yields 90°
torsion angles (Figure 3c), where both the aromatic
p orbital and nitrogen lone pair bisect the sulfonyl
(O=S=O) angle.
Again, the precise rotamer
conformation is further dictated by Nꢀalkyl
substitution and aromatic ortho substitution.
Examination of a sulfoxide moiety in the CSD
yielded dramatically less examples, nonetheless, a
pattern is emergent (Figure 3d) where torsion
angles between 75° and 105° were subtly preferred.
We synthesized an assortment of
molecules (4 – 9) containing a tꢀBu piperazine
moiety attached at the Cꢀ9 aryl position, varying
only the torsion functionality (See Supplemental
Information).
forging both
Past experience taught us that
hydrophobic and cationꢀpi
a
ACS Paragon Plus Environment

Page 3 of 6
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
interaction with Trp760 favored increased potency
Figure 4. 2.1Å coꢀcrystal structure of compound 8
bound to PI3Kγ             (used as a
surrogate for PI3Kδ).
and selectivity.9 Comparing examples 4 and 5
t
(Table 1), demonstrated that a highly basic Bu
piperazine increased biochemical potency for
PI3Kδ ten fold. While not optimal in terms of α/δ
selectivity (22 fold), the tꢀBu piperazine served as
an appropriate substituent to build SAR around
torsion angle preferences.
sulfoxide 8 yielded very high selectivity (α/δ = 184
fold) while the opposite Rꢀisomer 9 was moderately
selective and accompanied by erosion in PI3Kδ
potency (PI3Kδ = 11.6 nM). The Sꢀisomer of
sulfoxide 8 suggested two possible explanations for
increased potency and selectivity, 1) a preferred
rotamer is either 75° or 105°, and/or 2) the
sulfoxide moiety itself was responsible for making
new favorable (δ) and/or unfavorable (PI3Kα)
interactions. A coꢀcrystal structure of the Sꢀisomer
8 in PI3Kγ (0.596 ꢀM IC50 in PI3Kγ) revealed an
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. SAR of C9ꢀaryl benzoxazepin around
torsion angle preferences to achieve selectivity,
compounds 4-9.
experimental torsion angle of ~120°, effectively
t
positioning the Bu piperazine moiety to interact
with Trp760, making
a
favorable cationꢀpi
interaction (Figure 4). We were confident that the
preferred torsion angle was in the vicinity of 120°.
Not surprisingly, compounds 5 and 6 did not have
high α/δ selectivity (22 and 23 fold, respectively)
and was consistent with data found in the CSD
(Figure 3a and 3b) depicting low barriers of
rotation for 5 and a preferred 45° torsion angle for 6
which is not compatible with the binding pose of
Figure 5. Human liver microsome stability and
calculated lipohilicity for C8 vs C9 aryl substitution.
For our next round of design we incorporated
knowledge of lipophilicity and substituent effects
on metabolism in combination with torsion control.
In vitro human liver microsomes (HLM, Table 1)
indicated a range of predicted stabilities from
moderate to labile, with our most potent and
selective compound 8 predicted to have high
clearance (17 mL/min/kg). Analysis of HLM data
across the benzoxazepin series divided into four
bins (C8 vs C9 aryl substitution and cLogD <2 vs
cLogD >2) revealed trends that would influence
future designs (Figure 5aꢀd). HLM data showed a
higher percentage of stable to moderate stability for
C8ꢀaryl substituted benzoxazepin (Figure 5c and
5d). Furthermore, lipophilicity was a potential
contributor to HLM stability and suggested
compounds with a cLogD <2 could further reduce
the percentage of compounds exhibiting labile
human liver microsomal stability (Figure 5c) to
<5% when in conjunction with C8 substitution.
the Nꢀsubstituted piperazine.
Interestingly,
selectivity increased with sulfonamide 7 (α/δ = 78
fold) bearing a preferred torsion angle of 90°. The
Sꢀisomer of
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 4 of 6
1
2
3
4
5
8
X
O
N
These key learnings were applied towards
further optimization and our goal was to design a
series of molecules to meet the following three
criteria. First, target a dihedral torsion angle of
R
N
N
9
N
N
6
N
N
7
8
9
approximately 120° aimed at restricting the
conformation to interact with Trp760. Secondly,
design compounds that contain C8ꢀaryl substitution
to block potential metabolism. Lastly, design
targets in the desirable lipophilicity range (cLogD
<2) towards improving predicted human liver
microsomal stability.
Me
fold
selectivty
Kiapp (nM)
Entry
R
X
α/δ
PI3K-δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10 C-Me (R)-Me 0.48
11 C-Me (S)-Me 0.88
109
27
12
13
14
15
(R)-Me 0.78
C-F (S)-Me 2.4
479
102
28
C-F
(R)-Me 2.8
(S)-Me 1.9
N
N
113
Gratifyingly, PI3Kδ selectivity for all three pairs of
enantiomers, e.g. 10 RꢀMe α/δ = 109 and 15 SꢀMe
α/δ = 113 were greater than 100 fold. Most
notably, fluorine substituent, as in 12, achieved 479
fold α/δ selectivity.
Further profiling of
compounds 10, 12 and 15 (Table 3) revealed an
improved human liver microsomal stability for
pyridinyl compound 15 (<3.9 mL/min/kg).
Compound 15 also possessed the lowest cLogD
(1.29) and still maintained high permeability
(MDCK A to B = 10 x 10ꢀ6 cm/s) along with
excellent human whole blood potency (HWB = 28
nM).15
Figure 6. Computationally derived torsion scans for
hypothetical linkers a) C8ꢀaryl substitution and b) C8ꢀ
aryl and methylene substitution.
Dihedrals were
Table 3.
Human liver microsome stability,
permeability and human whole blood potency for
scanned from to 360 degrees in 10ꢀdegree
0
increments (See Supplemental Information for
computational method).
compounds 10-15.
MDCKc
CD69
Toward this end, a handful of bisꢀC8,C9ꢀ
aryl substituted benzoxazepin fragments were
evaluated computationally to derive energy/torsion
angle plots (Figure 6a). Preliminary designs
showed promise in reinforcing our desired torsion
angle of ~120°, especially for the Cꢀ8 fluorine and
methyl substituted analogs. A more pronounced
torsion restriction was achieved by the addition of a
methyl group to the methylene benzylic Cꢀ9
position (Figure 6b). The methyl substituent
alleviated 1,3ꢀstrain with the corresponding Cꢀ8
substitution.
Papp A to B HWBd
x10-6 cm/s IC50 (nM)
Entry cLogDa HLMb
10
12
15
2.3
1.9
1.3
8.4
15
14.2
13.6
10
4.9
15
<3.9
28
a MoKa v.2.6.5. bHuman hepatic clearance predicted from
human liver microsomes (stable <6, moderate 6-15, labile
>15 mL/min/kg). c Apparent permeability in MDCK
transwell culture. low <1, moderate 1-10, high >10. dSee
reference 14.
In summary, we have discovered a novel
benzoxazepin class of selective PI3Kδ inhibitors.
Through the aid of structure based design we
successfully applied our selectivity hypothesis,
derived from a structurally diverse morpholine
pyrimidine class, to target a unique “tryptophan
shelf” in PI3Kδ. Application to the benzoxazepin
class was achieved by evaluating dihedral torsion
angles both computationally and experimentally, in
an iterative process, to identify a low energy
conformation capable of achieving the desired
potency and selectivity. Ultimately, compound 15
containing bis C8, C9ꢀaryl substitution and a
cLogD <2 yielded a potent and selective PI3Kδ
inhibitor with low predicted human clearance, high
Analog synthesis was carried out
incorporating the three newly designed fragments
along with their corresponding enantiomers (See
Supplemental Information).
The biochemical
potency and selectivity is shown in Table 2.
Table 2. Potency and selectivity for C9 and C8
substituted benzoxazepins, compounds 10-15.
ACS Paragon Plus Environment

Page 5 of 6
ACS Medicinal Chemistry Letters
1
2
3
4
5
permeability and excellent human whole blood
potency.
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
*Brian S. Safina. Tel.: +1 650ꢀ467ꢀ7450, eꢀmail
address: bsafina@gene.com
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Author Contributions
All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Mengling Wong for purification of analogs.
ABBREVIATIONS
PI3K, phosphoinositideꢀ3ꢀkinase
REFERENCES
1. Yang, S.Y. Pharmacophore modeling and applications in drug discovery: challenges and recent advances.
Drug Discovery Today, 2010, 15, 444ꢀ450.
2. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in
Medicinal Chemistry. J. Med. Chem. 2015, 58 (21), 8315–8359.
3. Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A Survey of the
Role of Noncovalent Sulfur Interactions in Drug Design. J. Med. Chem. 2015, 58, 4383–4438.
4. Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. Feature Articles. Acta Cryst. 2016, B72, 171ꢀ179.
5. Allen, F. H. The Cambridge Structural Database: A Quarter of a Million Crystal Structures and Rising. Acta
Crystallogr., Sect. B: Struct. Sci. 2002, B58, 380ꢀ388.
6. Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. Small Molecule Conformational Preferences Derived
From Crystal Structure Data. a Medicinal Chemistry Focused Analysis. J. Chem. Inf. Model. 2008, 48, 1–24.
7. Cushing, T. D.; Metz, D. P.; Whittington, D. A.; McGee, L. R. PI3Kδ and PI3Kγ as Targets for Autoimmune
and Inflammatory Diseases. J. Med. Chem. 2012, 55, 8559–8581.
8. Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B. Exploiting the PI3K/AKT Pathway for Cancer
Drug Discovery. Nat Rev Drug Discov 2005, 4, 988–1004.
9. Sutherlin, D. P.; Baker, S.; Bisconte, A.; Blaney, P. M.; Brown, A.; Chan, B. K.; Chantry, D.; Castanedo, G.;
DePledge, P.; Goldsmith, P.; Goldstein, D. M.; Hancox, T.; Kaur, J.; Knowles, D.; Kondru, R.; Lesnick, J.;
Lucas, M. C.; Lewis, C.; Murray, J.; Nadin, A. J.; Nonomiya, J.; Pang, J.; Pegg, N.; Price, S.; Reif, K.;
Safina, B. S.; Salphati, L.; Staben, S.; Seward, E. M.; Shuttleworth, S.; Sohal, S.; Sweeney, Z. K.; Ultsch, M.;
Waszkowycz, B.; Wei, B. Potent and Selective Inhibitors of PI3Kδ: Obtaining Isoform Selectivity From the
Affinity Pocket and Tryptophan Shelf. Bioorg. Med. Chem. Lett. 2012, 22, 4296–4302.
10. Murray, J. M.; Sweeney, Z. K.; Chan, B. K.; Balazs, M.; Bradley, E.; Castanedo, G.; Chabot, C.; Chantry, D.;
Flagella, M.; Goldstein, D. M.; Kondru, R.; Lesnick, J.; Li, J.; Lucas, M. C.; Nonomiya, J.; Pang, J.; Price, S.;
Salphati, L.; Safina, B.; Savy, P. P. A.; Seward, E. M.; Ultsch, M.; Sutherlin, D. P. Potent and Highly
Selective Benzimidazole Inhibitors of PI3ꢀKinase Delta. J. Med. Chem. 2012, 55, 7686–7695.
11. Safina, B. S.; Sweeney, Z. K.; Li, J.; Chan, B. K.; Bisconte, A.; Carrera, D.; Castanedo, G.; Flagella, M.;
Heald, R.; Lewis, C.; Murray, J. M.; Nonomiya, J.; Pang, J.; Price, S.; Reif, K.; Salphati, L.; Seward, E. M.;
Wei, B.; Sutherlin, D. P. Bioorg. Med. Chem. Lett. 2013, 23, 4953–4959.
12. Heffron, T. P.; Heald, R. A.; Ndubaku, C.; Wei, B.; Augistin, M.; Do, S.; Edgar, K.; Eigenbrot, C.; Friedman,
L.; Gancia, E.; Jackson, P. S.; Jones, G.; Kolesnikov, A.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; McLean, N.;
Mörtl, M.; Nonomiya, J.; Pang, J.; Price, S.; Prior, W. W.; Salphati, L.; Sideris, S.; Staben, S. T.; Steinbacher,
S.; Tsui, V.; Wallin, J.; Sampath, D.; Olivero, A. G. The Rational Design of Selective Benzoxazepin
Inhibitors of the ΑꢀIsoform of Phosphoinositide 3ꢀKinase Culminating in the Identification of (S)ꢀ2ꢀ((2ꢀ(1ꢀ
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 6 of 6
1
2
3
4
Isopropylꢀ1
Hꢀ1,2,4ꢀTriazolꢀ5ꢀYl)ꢀ5,6ꢀDihydrobenzo[F]Imidazo[1,2ꢀD][1,4]Oxazepinꢀ9ꢀ
Yl)Oxy)Propanamide (GDCꢀ0326). J. Med. Chem. 2016, 59, 985–1002.
5
6
7
8
13. Ndubaku, C. O.; Heffron, T. P.; Staben, S. T.; Baumgardner, M.; Blaquiere, N.; Bradley, E.; Bull, R.; Do, S.;
Dotson, J.; Dudley, D.; Edgar, K. A.; Friedman, L. S.; Goldsmith, R.; Heald, R. A.; Kolesnikov, A.; Lee, L.;
Lewis, C.; Nannini, M.; Nonomiya, J.; Pang, J.; Price, S.; Prior, W. W.; Salphati, L.; Sideris, S.; Wallin, J. J.;
Wang, L.; Wei, B.; Sampath, D.; Olivero, A. G. Discovery of 2ꢀ{3ꢀ[2ꢀ(1ꢀIsopropylꢀ3ꢀMethylꢀ1Hꢀ1,2ꢀ4ꢀ
Triazolꢀ5ꢀYl)ꢀ5,6ꢀDihydrobenzo[F]Imidazo[1,2ꢀD][1,4]Oxazepinꢀ9ꢀYl]ꢀ1HꢀPyrazolꢀ1ꢀYl}ꢀ2ꢀ
Methylpropanamide (GDCꢀ0032): a ΒꢀSparing Phosphoinositide 3ꢀKinase Inhibitor with High Unbound
Exposure and Robust in Vivo Antitumor Activity. J. Med. Chem. 2013, 56, 4597–4610.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14. Staben, S. T.; Ndubaku, C.; Blaquiere, N.; Belvin, M.; Bull, R. J.; Dudley, D.; Edgar, K.; Gray, D.; Heald, R.;
Heffron, T. P.; Jones, G. E.; Jones, M.; Kolesnikov, A.; Lee, L.; Lesnick, J.; Lewis, C.; Murray, J.; McLean,
N. J.; Nonomiya, J.; Olivero, A. G.; Ord, R.; Pang, J.; Price, S.; Prior, W. W.; Rouge, L.; Salphati, L.;
Sampath, D.; Wallin, J.; Wang, L.; Wei, B.; Weismann, C.; Wu, P. Bioorg. Med. Chem. Lett. 2013, 23, 2606–
2613.
15. Baker, S. J.; Goldsmith, P.; Hancox, T. C.; Pegg, N. A.; Price, S.; Shuttleworth, S. J. WO 2007122410 A1.
Abstract graphic
ACS Paragon Plus Environment