Больше хороших молекул: скаффолд ... · 2020-01-29 · ( nerviano...
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Больше хороших молекул: скаффолд-ориентированный синтез для биомедицинских
приложений
Lecture 2. 1st Year Graduate students. 2016
Picture of the day
Once again: main points from the previous (intro) lecture
• medicinal chemistry
• drug target
• target identification
• target validation
• from validated target to pre-clinical candidate in ____ months
• any individual and pure organic compound is good for screening: TRUE/FALSE
• Lipinsky “RULE OF FIVE”
Quotation from the course synopsis
Основной дидактической целью курса является выработка у слушателей трех важнейших навыков: • понимания сложностей и особенностей принятия решений в многопараметрической медицинско-химической оптимизации • способности критически оценивать встречающиеся в литературе результаты • навыков дизайна собственных исследовательских проектов по разработке и оптимизации новых химических серий в различных терапевтических областях, на различных биологических мишенях + LOTS AND LOTS OF MEDCHEM AND DRUG DISCOVERY LINGO IDEA FOR A LECTURE: «Англоязычная терминология в медицинской химии и drug discovery: перспективы использования в русскоязычной практике»
Chemistry space projection on Biology space
Понятие скаффолда (scaffold)
SO
OR
R'
Скаффолд (темплат, хемотип)
Selective COX-2
inhibitors
O
SO
O
O
NN
SO
ONH2
F3C
ON
SO
ONH2
SBr
S OO
F
Vioxx(Merck)
Dup-679 Bextra (Pfizer)
Celebrex (Pfizer) 2013 sales >US$2.5B
WITHDRAWN
WITHDRAWN
Расположение периферии в пространстве Свойства соединения, «слабые места» Первоочередная основа для защиты интеллектуальной
собственности
Периферия
Принципы отбора синтетических идей в работу
Biological relevance
Novelty of scaffold
Novelty of chemistry
Elegance of synthetic approach
New environment for a known pharmacophore
Реакция Уги: от дипептоидов к разнообразным гетероциклам
NH2R1
O
R2
R3
R4OH
O
-CN+
R5
+N+H
R1
R3
R2
N+C-R5
R4
-O O
R3 R2
NH
R1N
O
R4
OR5
R4 N
O
R1
R3 R2HN
OR5• Суррогатные замены
• Бифункциональные реагенты
• Пост-конденсационные модификации
* *
* *
- H2O
Mumm rearrangement Многокомпонентная реакция
NH2
NH2
PhCHOt-BuNC N
NH2
Ph-C
N+
H+
NH
HN Ph
NH
DDQ, benzene
HClMeOH
r. t., 18 h
N
N Ph
NH
51% over 2 steps
2 X
HCl
dioxaner.t.
93%
N
N Ph
N
N Ph
NH2
N
NH
n-PrCHOt-BuNC
TMSClN
N Ph
NC-
N+
LA
69%
Krasavin et al. Synlett 2008, 645; JOC 2009, 74, 2627
2 МКР подряд ?
* *
NCNH
ONH2
O
TFA, dioxaner. t., 18 h
82%
NC
NH
NNH
O
O
NF3C O 0.5M HCl
MeOH60 oC, 18 h
74%
N
HNO
NH2
HNO
aq. K2CO3MeOH60 oC, 18 h
N
HNO
CF3
HNO
NC
69%NH
NNH
O
O
NF3C O
H+
NH
HN
NH
O
O
N F3CO
H+
- H2O
Krasavin et al. Tetrahedron Lett. 2010, 51, 4095
DOS – синтез, ориентированный на разнообразие
* *
OCHO H2N
NC HO
O
NHPh
O
+ O N
OPhHNOC
NHO
MeOH
r. t.
O N
O
ONH
O NHPh
68%
N
O
ONH
O NHPh
85% H3PO4 85% H3PO4
100 oC, 2 h88%
NN
O
O
O
OO
H
Krasavin et al. J. Org. Chem. 2006, 71, 9544
X
Тандем «реакция Уги – внутримолекулярное присоединение»
Мы в Википедии!
* *
S SO
SO O
SO
EWG
SO
EWG
OEWG
[O] [O]
[O]
- SO2
[O]
k1(DA) k2(DA)
k1(DA) >> k2(DA)
EWG EWG
Thiophene-S-oxide: IMDA and aromatization in one step?
* *
S O
S NH2
OO
COOHNH2
MeO
NC
MeOH, r. t., 20 h
OO
COOH
PhCHO
NC
O
O
S
NO
HN
MeO
O
OO
S N
OO
OO
NHO
O
m-CPBA (7 equiv.)DCM, r. t., 24 h
N
OO O
NHO
OMe29%(2 steps)
N
OO O
ONH
O
O
39%(2 steps)
Krasavin et al. Tetrahedron Lett. 2010, 51, 5657
S-ox
IMDA
S-ox
- SO2
- 2H
Thiophene containing Ugi adducts easily convert into isoindolinones
NH2
O
N NH2
O
NH2
OH2N
NH
N
H2N O
NH
ABT-888
NH
HN
F
OHN . H3PO4
AG014699
Poly(ADP-ribose)polymerase 1 (PARP1)
NAD+ bound to PARP-1
N+
R
NH2
O
NAD+
Tum
or w
eigh
t (g
)
Growth of mouse tumor xenograft
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 1 3 5 8 10 12
control Compound A (75 mpk) Compound B (75 mpk)
days
N
OO
R
N HH
R'
Isoindonlin-1-one PARP-1 inhibitors?
1. Papeo, G. M. E.; Krasavin, M.; Busel, A.; Khvat, A.; Forte, B.; Zuccotto, F. Oxo-2,3-dihydro-1H-isoindole-4-carboxamides as PARP Inhibitors.PCT Int. Appl. (2011), WO 2011006794, 69 pp.
2. Papeo, G. M. E.; Busel, A.; Casale, E.; Khvat, A.; Orsini, P.; Posteri, H.; Scolaro, A.3-Oxo-2,3-dihydro-1H-isoindole-4-carboxamides with selective PARP-1 inhibitions.PCT Int. Appl. (2011), WO 2011006803, 73 pp.
3. Papeo, G. M. E.; Borghi, D.; Caruso, M.; Posteri, H.; Krasavin, M. 3-Oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives as PARP-1 inhibitors. PCT Int. Appl. (2013) WO2013014038A1, 43 pp.
4. Papeo, G. M. E.; Orsini, P.; Scolaro, A.; Krasavin, M. Preparation of carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors. (Nerviano Medical Sciences) PCT Int. Appl. (2014), 60 pp. WO20142014064149A1.
“…These compounds show high oral bioavailability, good ADME properties and high tolerability. Selection of the candidate most suitable for further development is underway…”
Cancer Res, 2012,72, Supplement 1 doi: 10.1158/1538-7445.AM2012-1775 Proceedings: AACR 103rd Annual Meeting 2012-- Mar 31-Apr 4, 2012; Chicago, IL Abstract 1775: “Characterization of new highly selective and potent PARP-1 inhibitors “
Clinical candidate?
Visit our website: www.krasavin-group.org
Nadin, A. et al. Lead-Oriented Synthesis: A New Opportunity for Synthetic Chemistry. Angew. Chem. Int. Ed. 2012, 51, 1114-1122: «… Lead-oriented synthesis (LOS) is a new but simple concept describing reactions that allow the efficient preparation of diverse sets of small, polar molecules to act as starting points for drug discovery…»
В мире так мало … идеальных лид-соединений (leadlike compounds)!
Examples of compound synthesized:
(also under µwave irradiation)
Krasavin, M. Tetrahedron Lett. 2012, 53, 2876-2880.
HN
NRR
OHetArHal (1.1 equiv.)
Pd(OAc)2 (2 mol %)BINAP (4 mol %)
Cs2CO3 (1-3 equiv.)toluene, 100 oC, 16-20 h
N
NR
HetAr
H2NCH2CH2NH2
NBS
56-96% 49-93%
N
N
NF
N
N
N
N
N
NN
N
N
N
N
O
F
N
N
NNH2
(via NO2 --> NH2)
N-Heteroaryl imidazoline synthesis
Mw & cLogP on the right track!
0,0
1,0
2,0
3,0
4,0
5,0
6,0
0,0 100,0 200,0 300,0 400,0
N-Heteroaryl imidazolines cLogP
MW
Arachidonic acid cascade in inflammation
COX
COX
COX-1 COX-2
Consitutive enzyme Inducible enzyme
Inhibition undesired Selective inhibition is
highly desirable
Selective COX-2 inhibitors (coxibs)
O
SO
O
O
NN
SO
ONH2
F3C
ON
SO
ONH2
SBr
S OO
F
Vioxx(Merck)
Dup-679 Bextra (Pfizer)
Celebrex (Pfizer) 2013 sales >US$2.5B
N
N
SO
O
Cl
COX-2 IC50 = 0.24 µMCOX-1 IC50 > 100 µM
Khanna, I. K. et al. J. Med. Chem. 1997, 1634.
New synthesis of known imidazole COX-2 inhibitors gave us an idea
N
N
SO
O
Cl
COX-2 IC50 = 0.24 µMCOX-1 IC50 > 100 µM
NH
N
4-BrC6H4SO2Me (1.1 equiv.)Pd(OAc)2 (5 mol%)BINAP (10 mol%)Cs2CO3 (1.0 equiv.)toluene, 100 oC, 16-20 h
NN
NBS
DCM, 0 oC --> rt H
O
10% Pd-C
toluene, 100 oC36 h
SOO
NN
SOO
ClCl
Cl Cl
H2NNH2
Krasavin, M. Lett. Org. Chem. 2013, 10, 235
Khanna, I. K. et al. J. Med. Chem. 1997, 1634.
Can imidazolines inhibit COX-2?
N
N
SO
O
Cl
COX-2 IC50 = 0.24 µMCOX-1 IC50 > 100 µM
No substitution preferred
CH3 or CF3 increases COX-2 potency
H2NSO2 in lieu of Me sulphone preferred
Hal or MeO substitutions preferred
Searle (Pfizer) compound:
Pilot imidazoline library dsigned based on the SAR from Searle
NN
SO
R
OR'
R''
H, Me = = CH3, NH2
‘Best’ substitutions from Searle
Σ = 30 compounds LIGAND-BASED DESIGN
Pilot library synthesis
NH
N
4-BrC6H4SO2Me (1.1 equiv.)Pd(OAc)2 (5 mol%)BINAP (10 mol%)Cs2CO3 (1.0 equiv.)toluene, 100 oC, 16-20 h
NN
NBS
DCM, 0 oC --> rt H
O
SOO
R'
H2NNH2
R'
R'
R R
R
Pd(OAc)2 (5 mol%)BINAP (10 mol%)
Cs2CO3 (1.0 equiv.)toluene, 100 oC, 20 h
Br SO
ON(DMB)2
DMB =
O
O*
NN
SO
N(DMB)2
OR'
R
TFA, Et3SiH DCM, 0 oC--> r.t.
NN
SO
NH2
OR'
R
Σ = 30 compounds
R’’Ph Ar1 Ar2 Ar3 Ar4 Ar5 Ar6 Ar7 Ar8 Ar9 Ar10 Ar11 Ar12
R / R’
Me/H 7.1 6.8 8.1 2.1 3.6
Me/Me
NH2/H 6.9 3.4 2.9 7.2 2.5 9.5 6.2 6.7 0.3 1.8
NH2/Me
NN
SO
R
OR'
R''
SAR for imidazoline COX-2 inhibitors (IC50, µM)*
imidazolines clearly display a different SAR compared to Searle’s imidazoles the most active compound is comparable to Celebrex (IC50 = 0.11 µM) in terms of COX-2 inhibitory potency
* All compounds do NOT inhibit COX-1 even at 100 µM !
Animal efficacy of the lead compound
Control 3h post carageeenan injection
Plethysmometer
0
10
20
30
40
50
60
70
80
90
Control Treatment
MIKR06-27-1 3.7 mg/kg i.p.
PK profile of the lead compound
Plasma
Brain tissue
LC MS MS
Systemic exposure
Drug exposure in
CNS
Сmax = 16.6 µM (55 x IC50!) Сmax = 0.71 µM
(2 x IC50!)
CNS-expressed COX-2 is implicated as target for neuroinflammation COX-2 inhibitors that cross the BBB are needed to validate this approach
A case study of an effective drug discovery collaboration
Griffith U: project design and compound synthesis
UC Davis: biochemical testing
for COX-2/1 inhibition
MIPT: in silico modeling
Enamine/Beinta: mouse PK studies
Aristotelean U Greece: animal efficacy
Sarnpitak, P.; Mujumdar, P.; Morisseau, C.; Hwang, S. H.; Hammock, B.; Iurchenko, V.; Zozulya, S.; Gavalas, A.; Geronikaki, A.; Ivanenkov, Y.; Krasavin, M. Eur. J. Med. Chem. 2014, 84, 160-172.
1,3-Diarylindanes: guessing it right
F3C
Ar
Ar
O
CF3
TfOH20 °C, 1h
+R3
R2
R1
R2
R3
R1
R1
R2R3
F3C
Ar
R1
R2R3
Ar
OH
CF3
R3
R2R1
35-80%
cLogP ~ 6-8
NH
OHO
AEA
O
OHO
2-AG
HO
O
OH
H
H
∆9-THC
Prof. Vasiliev group (SPbSU)
1,3-Diarylindanes: guessing it right
N NHN
ON
Cl
Cl
Cl
SR141716A
N
O
JWH015
O
O
MeO
CN
OMe
LY320135
CB1 CB1 CB2
F3C
OMe
OMe
Cl
MeO
MeO
1,3-Diarylindanes: guessing it right 1 µM 10 µM
F3C
OMe
OMe
Cl
MeO
MeO
U Bern (Switzerland)
Concepts introduced or touched upon today molecular scaffold and compound’s periphery
clinically validated biological (therapeutic) target
lead-like compounds (“lead-likeness”)
potency and selectivity of drug candidate
chemistry and biology space
privileged scaffolds