Update on Malaria Libre Project Meeting - 19th April 2023
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Agenda
1.
Introduction: Malaria Libre series and next milestone (slides 3-4)
2.
Aryl Imidazole as main chemical series
(slides
5-11
)
3.
4-Aminothienopyridines (slide 12)
4.
Need for a new series? (slide 13)
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Main MMV criteria to be achieved
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Cytotoxicity >100-fold; hERG IC50 > 1 µM
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Minimum Inoculum for resistance > 10
6
-10
7
parasites
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Aqueous solubility > 10 µM (PBS); stable in plasma
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SCID in vivo efficacy
(ED90<50 mg/kg -> measure PD parameters and check consistency with MMVsola)
Detailed MMV criteria can be found through the link below:
https://www.mmv.org/research-development/information-scientists
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Need also to demonstrate potential for transition into lead optimization
3
Confidential
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Limited work
Current main series
*LipE = pIC50 - eLogD
4
MIR
>10
7
for all chemotypes
New Data
Parked
Transferred to
A. Vaidya/M. Riscoe
C. Friel’s lab
contribution
Chemistry r
esources appointed by MMV: 3 FTEs
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MMV1960432
Pf
3D7 IC
50
0.045
µM
LogD ~3.8; MW 426; tPSA 46
Limited modifications tolerated: indole and CF
3
/Cl imidazoles (but higher
LogD), azabenzimidazoles (some potency loss)
Not tolerated: unsubstituted imidazole, NMe imidazole, 1,2,4-triazole, pyrazole
Phenyl > Pyridine > Pyrazine
=> SAR divergence vs. MMV portfolio compounds
Indole, Benzoxazoles tolerated
To be further explored, appears to improve potency, shift vs Dd2 to be
monitored
Amenable to a variety of modifications (e.g. pyrrolidine derivatives + amide
moiety => improve physchem properties and Caco-2 permeability)
SAR summary
Main Issues
Metabolic stability, permeability and CYP
issues most likely related to the di-Me
imidazole core
Understand shift vs. Dd2
.
Difficult to rationalize
Include Dd2 in the test cascade along
with 3D7 testing
hERG to be monitored, especially for
imidazoles
Cytotoxicity to be monitored, especially
for compounds with LogD>3
5
6
MMV1965085
3D7 IC50 0.37
µ
M
Free IC50
0.0005
µ
M
Dd2 IC50
1.27
µM
HepG2
5.9
µM
Caco-2
0
Human mics
< 3.5
Rat heps
3.85
eLogD 5.12
Sol
2.5
µM
hERG IC50 12
µM
CYPs only 1A2 ~50% at 10
µ
M
Good metabolic stability despite high LogD
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MMV1965126
3D7 IC50 0.073
µ
M
Free IC50
0.001
µ
M
Dd2 IC50
0.77 µM
HepG2
4.9
µM
Caco-2
0
,
PAMPA 6.7
Human mics 26.2
Rat heps 22.1
eLogD 3.59
Sol
40.7
µM
MMV1981100
3D7 IC50
0.054
µM
Free IC50
0.0014
µM
HepG2
6.9
µM
PAMPA
48.1
Human mics 58.4
Rat heps 43.6
eLogD 4.38
Sol 29.3
µM
MMV1981184
3D7 IC50 0.52
µ
M
Free IC50
0.001
µM
Dd2 IC50
2.2
µM
HepG2
5.7
µM
Caco-2
0.7
Human mics 12.9
Rat heps 15.6
eLogD 5.27
Sol
2.5
µM
similar unbound IC50s
3D7 potency
Do not meet MMV early lead criteria
3D7 potency
Meets MMV early lead criteria
Ideally we would need to achieve physchem/DMPK properties to allow testing of 1 representative of
indoles and imidazoles in
in vivo
efficacy SCID mouse model to compare the relative in vivo MICs
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3D7 IC50 1.66
µ
M
ADME Tier 1
Albumax binding 53.99%
Free IC50 0.76
µ
M
Human mics
9.54
Rat heps
5.32
eLogD 1.6
Sol
110
µM
Same free IC50 as for the
diMe imidazole
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3D7 IC50
10.17
µ
M
Substituent detrimental
for activity
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3D7 IC50 1.86
µ
M
ADME Tier 1
Albumax binding 98.26%
Free IC50 0.032
µ
M
Human mics
4.09
Rat heps
3.49
eLogD 2.31
Sol
122
µM
Free IC50: 1 log more potent
Worth checking Dd2 and
permeability
MMV1992247
3D7 IC50 0.98
µ
M
Albumax binding 21.91%
Free IC50 0.76
µ
M
Dd2 IC50
17
µM
Human mics
4.84
Rat heps
2.74
eLogD 0.52
Sol
>200
µM
Would expect low permeability
Targets cancelled
Worth considering
azabenzimidazole with
pyrrolidine-piperidine
substituent?
Free 3D7 potency
Indole > DiMe-imidazole ~ benzimidazole
MMV1794348
3D7 IC50 0.119
µ
M
R=Cl (unsuccessful synthesis attempts)
R=OMe 10 mg with some formic acid
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MMV1965126
3D7 IC50 0.073
µ
M
Free IC50
0.001
µ
M
Dd2 IC50
0.77 µM
HepG2
4.9
µM
Caco-2
0
,
PAMPA 6.7
Human mics 26.2
Rat heps 22.1
eLogD 3.59
Sol
40.7
µM
MMV1992408
3D7 IC50
0.044
µ
M
Worth collecting Dd2
and albumax binding
ADME Tier 1
Permeability to assess
impact of potential
intramolecular H bond
MMV1992409
3D7 IC50
0.607
µ
M
Detrimental for 3D7
potency
MMV1991996
3D7 IC50
0.088
µ
M
Worth collecting Dd2
and albumax binding
ADME Tier 1
Flexible amine side-
chain tolerated at the
top part
MMV1960332
3D7 IC50 0.164
µ
M
MMV1794346
3D7 IC50 0.122
µ
M
Albumax 52.91%
Free IC50
0.053
µ
M
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MMV1991651
3D7 IC50 0.56
µ
M
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Compounds previously proposed by Iktos
MMV1991689
3D7 IC50 2.6
µ
M
MMV1991690
3D7 IC50 1.2
µ
M
New data
MMV1992248
3D7 IC50 1.96
µ
M
MMV1992626
: delivered
Perhaps worth considering more
flexibility at this position (also for
piperidine etc.)
MMV1991984
3D7 IC50 1.02
µ
M
Pyridyl tolerated as benzyl replacement?
This should allow a better understanding of the possible combinations between the top and right part of the molecule
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MMV1991985
3D7 IC50
15.6
µ
M
Initial routes (2) unsuccessful;
on-hold
Final compound under purification
Step 4 out of 5 unsuccessful,
on-hold
MMV1992279
3D7 IC50
>25
µ
M
Still priority compounds in the queue (see next slide)
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1
st
priority: Ideally
NH piperidine analogues
to be delivered for all of them (O-CH2-Ph-Cl as RHS for most cpds to establish if modifications tolerated)
Ongoing
Ongoing
4 steps
Alternative route initiated
8 steps
Step 5 out of 8-9 steps
Information about costs and
synthetic route for fluorinated
piperidine obtained but worth
prioritizing at a later stage
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Expect issues similar to the 4-aminoquinolines (e.g hERG liability)
•
ESAC strongly questioned the thienopyridine core due to the thiophene moiety as potential time-
dependent CYP inhibitor
Few analogues delivered by TCGLs to check whether the thiophene moiety can be replaced
while maintaining potency against Dd2 and piperaquine-resistant strains
Furan analogue: similar potency but would still expect liabilities
additional analogues to be exhaustive:
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6
4
3
6
1
3D7 IC50 0.036
µ
M
Free IC50 0.018
µ
M
Human mics 10.6
Rat heps 8
eLogD 2.5
Sol
171
µM
ES gams 0.107 µM
12
M
M
V
1
9
9
1
6
3
2
3D7 IC50 0.204
µ
M
ADME Tier1
Albumax binding 29.46%
Free IC50 0.144
µ
M
Human mics 3.88
Rat heps 10.29
eLogD 2.02
Sol
199
µM
M
M
V
1
9
9
1
6
8
8
3D7 IC50
0.060
µ
M
ADME Tier 1
Albumax binding 35.52%
Free IC50 0.039
µ
M
Human mics 6
Rat heps 12.11
eLogD 2.02
Sol
>200
µM
M
M
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1
9
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1
8
9
1
3D7 IC50
0.99
µ
M
M
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1
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1
9
2
6
3D7 IC50
1.08
µ
M
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?
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Risk mitigation strategy in case the arylimidazoles/indoles does not deliver
•
TC held on the 28
th
of March with Natalie, Tony and Takeshi (under CDA with MMV) to
evaluate remaining hits from MMV library hit generation activities
•
Interest expressed around a few series
•
Additional hit validation/profiling required and need for internal prioritization at MMV
before giving a new series to Malaria Libre
Cover page and welcome screen
The Malaria Libre Project Meeting held on 19th April 2023 discussed key topics such as the Aryl Imidazole chemical series, potential new series, and the MMV Early Lead Criteria for the next milestone. Chemistry resources appointed by MMV were also outlined, focusing on Aryl Imidazoles as the main area of research. The meeting highlighted the importance of achieving specific criteria for the Malaria Libre project and shared insights into the current progress and challenges faced in developing effective compounds for malaria treatment.
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Presentation Transcript
Malaria Libre Project Meeting 19th April 2023 1
Agenda 1. Introduction: Malaria Libre series and next milestone (slides 3-4) 2. Aryl Imidazole as main chemical series (slides 5-11) 3. 4-Aminothienopyridines (slide 12) 4. Need for a new series? (slide 13) 2
Reminder: MMV Early Lead Criteria Next milestone for Malaria Libre: Early Lead delivery by Q3 2023 Main MMV criteria to be achieved 3D7 EC50 < 100 nM (asexual blood stage); no shift vs resistant strains or cross-resistance panel Cytotoxicity >100-fold; hERG IC50 > 1 M Minimum Inoculum for resistance > 106-107 parasites Aqueous solubility > 10 M (PBS); stable in plasma In vivo rodent PK: Bioavailability >20% (using stable suspension/solution in acceptable vehicle) SCID in vivo efficacy (ED90<50 mg/kg -> measure PD parameters and check consistency with MMVsola) Detailed MMV criteria can be found through the link below: https://www.mmv.org/research-development/information-scientists Need also to demonstrate potential for transition into lead optimization 3
Chemistry resources appointed by MMV: 3 FTEs Malaria Libre Series Transferred to A. Vaidya/M. Riscoe C. Friel s lab contribution Current main series Parked Limited work Confidential MMV1964359 Aminopyridinol 0.003, 0.007 / 4.7 0.0005 / 5.5 ~4 (Fast) pending ND MMV1804508 Cyclopropyl amide 0.19,0.07 / 2.9 pending 3.8 (Slow, lag phase) 9.7 (SI~51) 0.29 (Pb) MMV1964361 4-aminothienopyridine 0.036 / 4.9 0.018 / 5.2 ND pending ND MMV1919978 Phenyl amide 0.13, 0.35 / 4.1 0.005 / 5.5 ~4 (Fast) 8.5 (SI~70) ND (Pb: analogs active) MMV1960432 Aryl imidazole 0.045, 0.040 / 3.5 pending Compound Scaffold PfIC50 LDH (3D7,Dd2 M)/ LipE* Free potency ( M) / LipE* PRR (representative compound) ~3-4 (Moderate-Fast) Cytotoxicity (HepG2, M) Potency (liver stages, M) >25 ND DGFA/ : 0.87/>25 DGFA inactive ES gams 0.107 M ES gams 0.085 M ND (analogs inactive) Potency (transmission, M) 3.8 161 2.8 46 3.8 7.5 3.8 8.9 2.5 171 eLogD Solubility (PBS), M CACO-2 (ER; AB; BA) Microsome (h) Clint Hepatocyte (r) Clint CYP Inhibition %I @10uM hERG (K+CHO) EC50, M 27.6; 0.05; 1.43 19 56 ND (analogs inhibitors) 3.7 619; 0.01; 7.38 <3.5 13 <50% 1.4 1.6; 4.2, 6.9 33 139 <2% 10.3 1.8; 2.3, 4.3 245 92 ND ND 7.7; 0.02, 0.16 10.6 8 ND 1.6 for analog New Data *LipE = pIC50 - eLogD 4 MIR>107 for all chemotypes
Aryl imidazoles: Main Focus of MMV chemistry resources SAR summary Main Issues Metabolic stability, permeability and CYP issues most likely related to the di-Me imidazole core Understand shift vs. Dd2. Difficult to rationalize Include Dd2 in the test cascade along with 3D7 testing MMV1960432 Pf 3D7 IC500.045 M LogD ~3.8; MW 426; tPSA 46 Limited modifications tolerated: indole and CF3/Cl imidazoles (but higher LogD), azabenzimidazoles (some potency loss) Not tolerated: unsubstituted imidazole, NMe imidazole, 1,2,4-triazole, pyrazole hERG to be monitored, especially for imidazoles Phenyl > Pyridine > Pyrazine => SAR divergence vs. MMV portfolio compounds Indole, Benzoxazoles tolerated Cytotoxicity to be monitored, especially for compounds with LogD>3 To be further explored, appears to improve potency, shift vs Dd2 to be monitored Amenable to a variety of modifications (e.g. pyrrolidine derivatives + amide moiety => improve physchem properties and Caco-2 permeability) 5
Reminder: Aryl Imidazoles vs Aryl Indoles MMV1965085 3D7 IC50 0.37 M Free IC50 0.0005 M Dd2 IC50 1.27 M HepG2 5.9 M Caco-2 0 Human mics < 3.5 Rat heps 3.85 eLogD 5.12 Sol 2.5 M hERG IC50 12 M CYPs only 1A2 ~50% at 10 M Good metabolic stability despite high LogD 3D7 potency Do not meet MMV early lead criteria MMV1981184 3D7 IC50 0.52 M Free IC50 0.001 M Dd2 IC50 2.2 M HepG2 5.7 M Caco-2 0.7 Human mics 12.9 Rat heps 15.6 eLogD 5.27 Sol 2.5 M MMV1981100 3D7 IC50 0.054 M Free IC50 0.0014 M MMV1965126 3D7 IC50 0.073 M Free IC50 0.001 M Dd2 IC50 0.77 M HepG2 4.9 M Caco-2 0, PAMPA 6.7 Human mics 26.2 Rat heps 22.1 eLogD 3.59 Sol 40.7 M HepG2 6.9 M PAMPA 48.1 Human mics 58.4 Rat heps 43.6 eLogD 4.38 Sol 29.3 M similar unbound IC50s 3D7 potency Meets MMV early lead criteria Ideally we would need to achieve physchem/DMPK properties to allow testing of 1 representative of indoles and imidazoles in in vivo efficacy SCID mouse model to compare the relative in vivo MICs 6
Aryl Imidazoles: Targets proposed by Tony Mete based on SAR / ADME properties MMV1991768 3D7 IC50 10.17 M MMV1992247 3D7 IC50 0.98 M Albumax binding 21.91% Free IC50 0.76 M Dd2 IC50 17 M Human mics 4.84 Rat heps 2.74 eLogD 0.52 Sol >200 M MMV1991824 3D7 IC50 1.66 M ADME Tier 1 Albumax binding 53.99% Free IC50 0.76 M Human mics 9.54 Rat heps 5.32 eLogD 1.6 Sol 110 M MMV1991925 3D7 IC50 1.86 M ADME Tier 1 Albumax binding 98.26% Free IC50 0.032 M Human mics 4.09 Rat heps 3.49 eLogD 2.31 Sol 122 M Targets cancelled Substituent detrimental for activity Worth considering azabenzimidazole with pyrrolidine-piperidine substituent? Would expect low permeability Same free IC50 as for the diMe imidazole Free IC50: 1 log more potent Worth checking Dd2 and permeability MMV1794348 3D7 IC50 0.119 M R=Cl (unsuccessful synthesis attempts) R=OMe 10 mg with some formic acid Free 3D7 potency Indole > DiMe-imidazole ~ benzimidazole 7
Aryl Imidazoles: new data MMV1992408 3D7 IC50 0.044 M MMV1965126 3D7 IC50 0.073 M Free IC50 0.001 M Dd2 IC50 0.77 M HepG2 4.9 M Caco-2 0, PAMPA 6.7 Human mics 26.2 Rat heps 22.1 eLogD 3.59 Sol 40.7 M MMV1992409 3D7 IC50 0.607 M MMV1960332 3D7 IC50 0.164 M MMV1991996 3D7 IC50 0.088 M MMV1794346 3D7 IC50 0.122 M Albumax 52.91% Free IC50 0.053 M Worth collecting Dd2 and albumax binding ADME Tier 1 Detrimental for 3D7 potency Worth collecting Dd2 and albumax binding ADME Tier 1 Permeability to assess impact of potential intramolecular H bond Flexible amine side- chain tolerated at the top part 8
Aryl Imidazoles: New Data Compounds previously proposed by Iktos New data Perhaps worth considering more flexibility at this position (also for piperidine etc.) MMV1991690 3D7 IC50 1.2 M MMV1991984 3D7 IC50 1.02 M MMV1991651 3D7 IC50 0.56 M MMV1991689 3D7 IC50 2.6 M Pyridyl tolerated as benzyl replacement? MMV1992248 3D7 IC50 1.96 M MMV1992626: delivered This should allow a better understanding of the possible combinations between the top and right part of the molecule
Aryl Imidazoles: Latest selection of targets proposed by Iktos MMV1992279 3D7 IC50 >25 M MMV1991985 3D7 IC50 15.6 M Step 4 out of 5 unsuccessful, on-hold Initial routes (2) unsuccessful; on-hold Final compound under purification Still priority compounds in the queue (see next slide) 10
Aryl Imidazoles: Target Compounds currently prioritized 1st priority: Ideally NH piperidine analogues to be delivered for all of them (O-CH2-Ph-Cl as RHS for most cpds to establish if modifications tolerated) Information about costs and synthetic route for fluorinated piperidine obtained but worth prioritizing at a later stage Ongoing 8 steps Ongoing 4 steps Alternative route initiated Step 5 out of 8-9 steps 11
4-Aminothienopyridines Expect issues similar to the 4-aminoquinolines (e.g hERG liability) ESAC strongly questioned the thienopyridine core due to the thiophene moiety as potential time- dependent CYP inhibitor Few analogues delivered by TCGLs to check whether the thiophene moiety can be replaced while maintaining potency against Dd2 and piperaquine-resistant strains MMV1964361 3D7 IC50 0.036 M Free IC50 0.018 M Human mics 10.6 Rat heps 8 eLogD 2.5 Sol 171 M ES gams 0.107 M MMV1991632 3D7 IC50 0.204 M ADME Tier1 Albumax binding 29.46% Free IC50 0.144 M Human mics 3.88 Rat heps 10.29 eLogD 2.02 Sol 199 M MMV1991891 3D7 IC50 0.99 M MMV1991926 3D7 IC50 1.08 M MMV1991688 3D7 IC50 0.060 M ADME Tier 1 Albumax binding 35.52% Free IC50 0.039 M Human mics 6 Rat heps 12.11 eLogD 2.02 Sol >200 M Furan analogue: similar potency but would still expect liabilities additional analogues to be exhaustive: 12
Need for a New Series for Malaria Libre? Risk mitigation strategy in case the arylimidazoles/indoles does not deliver TC held on the 28th of March with Natalie, Tony and Takeshi (under CDA with MMV) to evaluate remaining hits from MMV library hit generation activities Interest expressed around a few series Additional hit validation/profiling required and need for internal prioritization at MMV before giving a new series to Malaria Libre 13
