Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character

Article abstract of DOI:10.1021/acsmedchemlett.0c00039

The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp3 rich scaffolds for use in drug discovery programs. Here we report the design, synthesis, and computational structural analysis of a series of 2,4-methanoprolines having inherent 3D character (PMI and PBF scores) significantly higher than that of the broader AbbVie Rule of 3 (Ro3) collection.

Full text of DOI:10.1021/acsmedchemlett.0c00039

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Letter
Escaping from Flatland: Substituted Bridged Pyrrolidine
Fragments with Inherent Three-dimensional Character.
Brian Cox, Victor Zdorichenko, Philip B. Cox, Kevin I. Booker-Milburn, Romain
Paumier, Luke D. Elliott, Michael Robertson-Ralph, and Graham Bloomfield
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.0c00039 • Publication Date (Web): 27 Mar 2020
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Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments
with Inherent Three-dimensional Character.
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Brian Cox,*,†, ‡ Victor Zdorichenko,‡ Philip B. Cox,*,¶ Kevin I. Booker-Milburn,§,# Romain Paumier, ‡
Luke D. Elliott,§ Michael Robertson-Ralph,# and Graham Bloomfield†
†School of Life Sciences, University of Sussex, Brighton, BN1 9QJ, U.K.
‡Photodiversity Ltd, c/o School of Life Sciences, University of Sussex, Brighton, BN1 9QJ, U.K.
§School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, U.K.
#Photodiversity Ltd, c/o School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, U.K.
¶Drug Discovery Science and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-6217,
U.S.A.
KEYWORDS: Drug discovery, photochemistry, sp3 rich scaffolds, substituted bridged pyrrolidine fragments, 3D character.
ABSTRACT: The pressure to deliver new medicines to the patient continues to grow along with increases in compound
failure rate; thus, putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of
potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many
workers have taken a new look at the power of photochemistry, as a means to generate novel sp3 rich scaffolds for use in
drug discovery programs. Here we report the design, synthesis and computational structural analysis of a series of 2,4-
methanoprolines having inherent 3D character (PMI and PBF Scores) significantly higher than that of the broader AbbVie
Rule
of
3
(Ro3)
collection.
In their seminal paper entitled “Escape from Flatland:
Increasing Saturation as an Approach to Improving Clinical
Success” Lovering et al hypothesized that the shift to high-
throughput synthetic practices had resulted in more
achiral, aromatic compounds.1 This was supported by
Walters et al who analysed the types of molecules that had
been made by medicinal chemists over the 50 years
preceding 2009. It showed quite conclusively the dramatic
rise in the proportion of molecules containing sp2 - sp2
couplings. The authors attributed this trend away from sp3
character to the introduction of new methods for sp2 - sp2
couplings, and the adaptation of these methods to high-
throughput synthesis, utilised widely in optimisation
programs and in archive “enrichment” campaigns (Figure
1).2
In a later paper, Lovering described how increasing
complexity reduces promiscuity and Cyp450 inhibition.
Increased promiscuity has been linked to toxicity and
candidate failure.3
Lovering et al focussed on carbon bond saturation as
defined by fraction sp3 (Fsp3) where Fsp3 = (number of sp3
hybridized carbons/total carbon count) as a simple and
interpretable measurement of the complexity of molecules
prepared as potential drug candidates. They went on to
demonstrate that complexity (as measured by Fsp3)
correlates with success as compounds transition from
discovery, through clinical testing, to drugs (see Figure 2).
They further demonstrated that saturation correlates with
solubility, an experimental physical property important to
success in the drug discovery setting.1
Figure 1. Influence of sp2 – sp2 coupling chemistries on the
molecules published in the Journal of Medicinal Chemistry
between 1959 and 2009. Data are shown as the fraction of
molecules published in each 5-year period containing at least
one acyclic–aromatic carbon–carbon bond. Reprinted from ref
(2). Copyright 2011, American Chemical Society.
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Reagents and conditions: (a) Allylamine then AcCl, Et3N,
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Figure 2. Mean Fsp3 for compounds in different stages of
development. **P value <0.001. Reprinted from ref (1).
Copyright 2009, American Chemical Society.
benzene (22%); (b) hv, acetone (55%); (c) Aq. KOH (72%);
(d) PhCOCl, Et3N, DCM, then NaH, allyl Br, DMF (80%); (e)
hv, acetophenone, MeCN (88%); (f) 6 N HCl (99%).
Further to the positive impact of increasing fraction sp3
(Fsp3) on attrition rates, Clemons et al examined
compounds from different sources (commercial, academic,
natural) for their protein-binding behaviours and found
that these behaviours correlate with general trends in
stereochemical and shape descriptors for these compound
collections. Increasing the content of sp3-hybridized and
stereogenic atoms relative to compounds from commercial
sources, which comprise the majority of current screening
collections, improved binding selectivity and frequency.4
Figure 3. 4-Substituted 2,4-methanoproline analogues
N-1, 2-substituent variations. The N-benzoyl, ethyl ester
of 2,4-methanoproline 6 was prepared by the method of
Malpass et al.11 This compound was used to prepare a
diverse range of proline derivatives; the 2-hydroxylmethyl
7, the 2-methoxylmethyl 8 and the 2-carboxamido 9
analogues (Scheme 2), from which a novel array of N-
substituted amides and ureas were prepared using parallel
synthesis methods (Table 1).
A well-established approach to the generation of high
quality small molecular weight leads for drug discovery
programs is by the application of fragment based methods.
We were prompted to look at synthetic methodologies that
could be utilised to efficiently generate novel, complex, sp3
rich fragments. For a number of years, we have been
investigating the use of photochemistry, in particular [2+2]
cycloadditions, as a source of desirable starting points for
medicinal chemistry.5 We have, like other workers,
focussed some of our efforts on analogues of 2,4-
methanoproline 1. 2,4-methanoproline 1 was first isolated
from the seeds of Ateleia herbert smithii Pittier, a tree
found in Costa Rica,6 and is prepared in a simple sequence
of reactions from ethyl pyruvate 2 or serine 3 (Scheme 1)
Scheme 2. Synthesis of 2-substituent variations of 2,4-
methanoproline.
OH
N
c
10-20
R1
O
OEt
OH
OH
a
b
N
N
N
H
OMe
O
O
N
7
21-27
R1
O
N
6
c
via intramolecular [2
+ 2] olefin photocycloaddition
d
e
reactions.7,8 The utility and conformational properties of
2,4-methanoproline 1 as a replacement for D- or L-proline
has been studied, its N-acetyl, methyl ester was found to
show a large prevalence for a trans-amide conformation
more akin to primary amino acids than to D- or L-proline.9
This makes it a potentially interesting amino acid for
inclusion in therapeutic peptides and the basis for the
design of fragment libraries. A number of 2-position
variants of 2,4-methanoproline have been reported
recently10 and a small number of 4-substituted analogues,
such as the 4-methyl 4 and 4-fluoro 5 derivatives (Figure
3).9 We embarked on the synthesis of novel 2-substituted
and 2,4-substituted analogues of interest in their own right
but which were further utilised to prepare diverse N-
substituted amide and urea parallel libraries with a view to
exploring their utility as fragments in a screening library.
The compounds were designed to examine the three-
dimensional molecular shape and vectors produced by
extended substituents at the N-1, 2 and 4-postions.
OMe
g
c
OH
OMe
OMe
f
HN
O
N
N
N
H
28
HCl
H
O
8
h
N
N
OH
i
j
NH2
NH2
NH2
N
N
H
N
O
O
O
29-40
O
O
O
R1
O
O
O
9
k
NH2
N
O
HN
O
41
F
Reagents and conditions: (a) LiAlH4, THF (78%); (b)
Ammonium formate, Pd/C, EtOH (94%); (c) DIPEA, HATU,
DCM, R1 amine (See Table 1 for yields) ; (d) 6 N HCl (76%);
(e) NaH, MeI, THF (81%); (f) Ammonium formate, Pd/C,
EtOH (92%); (g) 4-Isocyanopyridine, DCM (39%); (h)
CbzCl, aq. Na2CO3, (80%); (i) Aq. Ammonia, HATU DIPEA,
Scheme 1. Synthesis of 2,4-methanoproline 1
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DCM (80%); (j) Ammonium formate, Pd/C, EtOH (90%);
(k) 2-Flurobenzyl isocyanate, DCM (44%).
1
2
O
N
N
3
4
5
6
N
Table 1. N-1 Amide derivatives of 2-substituent variations of
2,4-methanoproline.
19 (33%)
38 (36%)
NH2
OH
OMe
N
N
N
N
7
N
O
8
R1
O
R1
O
R1
O
N
9
Compound
number
(Yield%)
20 (47%)
Compound
number
(Yield%)
O
Compound
number
(Yield%)
39 (29%)
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N
N
N
40 (43%)
10 (59%)
29 (60%)
21 (49%)
N
N
N
N
O
F
N-1, 2,4-substituent variations. The 4-carboxylic acid
derivative of 2,4-methanoproline was prepared as its N-
benzoyl, 4-ethyl, 2-methyl diester 42 by the method of
Esslinger et al.12 This compound was used to prepare the
4-fluoromethyl derivative 43 and the 4-fluromethyl-2-
hydroxylmethyl derivative 44 (Scheme 3), from which a
further novel array of N-substituted amides were prepared
using parallel synthesis methods (Table 2). This sequence
involved the selective saponification of the 4-ethyl ester in
the presence of the 2-methyl ester using lithium hydroxide
in a THF water mixture, followed by selective reduction of
the carboxylic acid function and fluorination of the alcohol
product.
11 (31%)
30 (70%)
22 (40%)
F
N
N
O
12 (47%)
31 (33%)
23 (65%)
N
HN
F
32 (32%)
13 (62%)
F
24 (50%)
F
N
O
N
F
Scheme 3. Synthesis of 2,4-substituent variations of 2,4-
methanoproline.
33 (56%)
14 (54%)
25 (54%)
26 (63%)
N
F
34 (62%)
F
15 (51%)
F
N
O
N
16 (42%)
35 (64%)
27 (61%)
H
N
36 (71%)
17 (56%)
Reagents and conditions: (a) LiOH, THF/H2O (84%); (b)
BH3THF, THF (84%); (c) DAST, DCM (68%); (d) TFA, H2O
(43%); (e) DIPEA, HATU, DCM, R1 amine (See Table 2 for
yields); (f) LiAlH4, THF then Ammonium formate, Pd/C,
EtOH (40%).
F
O
37 (74%)
18 (60%)
Table 2. N-1 Amide derivatives of 2,4-substituent variations
of 2,4-methanoproline.
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F
F
were then used in combination to map the 3-dimensional
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2
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7
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space of these compounds. Plotting the sum of the
normalized PMIs versus the PBF score, the compounds
within the region of the graph defined by NPR (Sum of
the Normalized Principal Moments of Inertia (NPR1 and
NPR2)) ≥ 1.07 and PBF Score ≥ 0.6 are deemed, by Firth et
al, to reside in 3D space by virtue of two independent 3D
descriptors. Figure 4 shows this plot for 54 of the bridged
pyrrolidines, with the corresponding unfunctionalized
methanoproline intermediates labelled. Note that the
shape was assigned using an approximation based on the
relative values of NPR1 and NPR2.
OH
OH
N
N
O
R1
O
R1
O
Compound
number
(Yield%)
Compound
number
(Yield%)
9
N
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N
O
54 (48%)
45 (44%)
F
46 (50%)
Cl
N
O
55 (48%)
F
47 (38%)
56 (47%)
O
N
O
48 (49%)
O
57 (50%)
N
F
F
49 (45%)
58 (35%)
F
O
N
50 (24%)
59 (49%)
Figure 4. Plot of the normalized PMI versus PBF score for all
54 fragments.
F
F
F
All but 5 of these fragments sit in 3D space with all of the
intermediates resting comfortably in this region of space.
A comparison of the relative level of 3-dimensionality with
other fragments within the AbbVie Ro3 fragment collection
is shown in Figure 5.
51 (45%)
60 (45%)
F
61 (59%)
52 (28%)
O
F
53 (34%)
62 (37%)
63 (41%)
Computational Analysis
In order to investigate the in-silico properties of these
molecules, the structures were uploaded into AbbVie’s
design platform. In addition to a range of physicochemical
properties, the Principal Moments of Inertia (PMI) and the
Plane of Best Fit (PBF) scores were calculated using
methods described in the literature.13,14 These descriptors
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Figure 5. The % of compounds in 3D space for AbbVie’s Ro3
fragment library vs bridged pyrrolidines.
1
Conclusion. Over the coming 5-10 years the predicted
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positive impact of researchers synthesizing compounds
with higher Fsp3 in drug discovery programs will become
further apparent. Photocycloaddition reactions stand to
play a significant part in generating highly desirable
templates such as the 2,4-methanoproline derivatives
covered here. Our computational analysis clearly
demonstrates that fragments derived from 2,4-
methanoproline have inherent 3D character using two
independent 3D descriptors (PMI and PBF Score) and that
the degree of shape and 3D character may be prospectively
designed and biased towards fragments with enhanced 3D
character, residing in distinct property space to that
largely occupied by conventional screening libraries, thus
enabling the “escape from flatland”.
Overall the % of 3D character of the bridged pyrrolidines is
significantly higher (91%) than that of the broader AbbVie
Rule of 3 (Ro3) collection (58%) which is testament to the
proclivity of this scaffold to produce compounds with a
higher degree of 3D character within Ro3 chemical space.
This is similar to pyrrolidines which are common scaffolds
in drugs and known to enhance the 3D nature of
fragments, with enabling chemistries employed to
maximize both 2 and especially 3D diversity of fragment
space.15 It is interesting to note that the unsubstituted
methanoproline intermediates are highly saturated with
proportionate levels of Fsp3, however for the majority of
the corresponding substituted amide products, the level of
3 dimensionality increases as the level of saturation
decreases.
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ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the
ACS Publications website at DOI:
Synthetic methods, characterization, crystallographic and
computational modeling data.
AUTHOR INFORMATION
Corresponding Author
* E-mail: b.cox@sussex.ac.uk or
contact@photodiversity.uk.com
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare the following competing financial
interest(s): PBC is an employee of Abbvie. BC and KIBM are
employees of their respective universities, co-founders and
owners of Photodiversity Ltd. The design, study content, and
financial support for the study were provided by AbbVie.
AbbVie participated in the interpretation of data, review, and
approval of the publication.
Figure 6. Comparison of Fsp3 versus PBF score for the
methanoprolinol (compound 7) derived series.
As an example, we analysed the series of compounds from
the methanoprolinol derivative (compound 7) and plotted
Fsp3 versus PBF score. While the unsubstituted prolinol is
fully saturated (Fsp3=1), the corresponding amide
products have lower levels of saturation (Fsp3 <1),
however in many cases they possess higher degrees of 3-
dimensionality (see Figure 5). The 3D structures of the
corresponding conformations used to calculate the 3D
descriptors were visualized using Cresset’s ForgeTM
platform. It was evident from these 3D structures why
compound 19 possessed a higher degree of 3D character
with a sphere-like conformation, while compound 13 is a
flatter, more rod-like shape. This demonstrates that Fsp3
should be used with caution when describing the relative
3-dimensionality of compounds Overall these bridged
pyrrolidines possess inherent 3D character and allow for
the addition of fragments with higher degrees of favorable
3-dimesionality. In addition, this method opens the door to
prospective tailoring of the 3D character of the fragment
library prior to synthesis.
Funding Sources
We gratefully acknowledge support for Luke Elliott from the
Engineering and Physical Sciences Research Council
(EP/P013341/1).
ACKNOWLEDGMENTS
The authors wish to thank the following colleagues for
providing small molecule analysis data. Dr Alaa Abdul-Sada
(high resolution mass spectrometry), Dr Iain Day (NMR) and
Dr Mark Roe (X-ray crystallography). We are also grateful to
the Universities of Sussex and Bristol.
ABBREVIATIONS
DAST, Diethylaminosulfur trifluoride; DCM, dichloromethane;
DMF, Dimethylformamide; DIPEA, diisopropylethylamine;
HATU
1-[Bis(dimethylamino)methylene]-1H-1,2,3-
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(9) Mykhailiuk, P. K.; Kubyshkin, V.; Bach, T.; Budisa, N.
triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; THF,
tetrahydrofuran.
Peptidyl-Prolyl Model Study: How Does the Electronic
Effect Influence the Amide Bond Conformation? J. Org.
Chem. 2017, 82, 8831-8841.
1
2
3
4
5
6
7
8
9
(10) Levterov, V. V.; Michurin, O.; Borysko, P. O.; Zozulya, S.;
Sadkova, I. V.; Tolmachev, A. A.; Mykhailiuk, P. K.
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ACS Medicinal Chemistry Letters
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ACS Medicinal Chemistry Letters
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ACS Medicinal Chemistry Letters
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