Advanced Medicinal Chemistry - unipi.itomero.farm.unipi.it/matdidFarm/23/AMC_slides_A_171013.pdf ·...
Transcript of Advanced Medicinal Chemistry - unipi.itomero.farm.unipi.it/matdidFarm/23/AMC_slides_A_171013.pdf ·...
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Advanced Medicinal Chemistry
Filippo Minutolo
CFU 3 (21 hours)
Educational objectives
To provide the knowledge of:
1) the “chemistry” involved in the action of drugs and prodrugs thereof;
2) the structural considerations in the molecular design.
Recommended basic knowledge
General Chemistry, Organic Chemistry, Medicinal Chemistry
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Program
• “Drug-likeness”, ADMET, interactions
• Prodrugs: structural design, types of activation (enzymatic/nonenzymatic)
• Soft drugs
• “Intelligent” prodrugs: hypoxia-selective chemotherapeutics;
selective activations (ADEPT, ADAPT, MDEPT, etc.)
• Molecular complexity, pharmacoforic elements and synthetic accessibility
Advanced Medicinal Chemistry
Filippo Minutolo
CFU 3 (21 hours)
• Correlations between chemical features and biological properties
• The “chemistry” behind the action of a drug
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Reference textbooks and articles
R. B. Silverman “Organic Chemistry of Drug Design and Drug Action”, 2nd Edition,
Elsevier - Academic Press, San Diego, CA - USA, 2004. [ISBN 0-12-643732-7]
C. G. Wermuth “The Practice of Medicinal Chemistry”, 3rd Edition,
Elsevier – Academic Press, London, UK, 2008. [ISBN 0-12-744481-5]
Scientific articles from the recent literature, which will be provided during classes.
T. L. Lemke, D. A. Williams “Foye’s Principles of Medicinal Chemistry” (7th Ed.),
Lippincott Williams & Wilkins, 2013. [ISBN 978-1-60913-345-0]
E. H. Kerns, L. Di. “Drug-like Properties: Concepts, Structure Design and Methods”,
Elsevier - Academic Press, San Diego, CA - USA, 2008. [ISBN 978-0-1236-9520-8]
G. L. Patrick “An Introduction to Medicinal Chemistry” (5th Ed.), Oxford University
Pressi, 2013. [ISBN 978-0-19-969739-7]
Advanced Medicinal Chemistry
Filippo Minutolo
CFU 3 (21 hours)
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Vancomycin
Glycopeptidic antibiotic
Chem. Rev. 2005, 105, 425-448.
aglicone still active
inhibition of peptidoglycan biosynthesis
alteration of bacterial membrane permeability
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mechanism of action and resistance
complexation with tripeptide
(N-Ac-L-Lys-D-Ala-D-Ala)
peptidoglycan precursor
Chem. Rev. 2005, 105, 425-448.
mutation
(N-Ac-L-Lys-D-Ala-D-Lac)
resistance
Vancomycin
sensible bacteria
resistant bacteria
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Chem. Rev. 2005, 105, 425-448.
HN
O
HN
O
O
repulsione
O
O
convivenza
vancomicina
D-Ala-D-Lac D-Ala-D-Lac
vancomicina de-ossigenata
sensible bacteria
resistant bacteria
mechanism of action and resistance
Vancomycin
mutation
(N-Ac-L-Lys-D-Ala-D-Lac)
resistance
vancomycin de-oxygenated vancomycin
repulsion tolerance
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structural modification (O-off!) against resistant bacteria
J. Am. Chem. Soc. 2006, 128, 2885-2892.
OH
OO
NH
HN
H
O
N
H2N
O
O
NH
OH
Cl
O
NHMeHN
ClO
N
O H H
H
HOOCH
HO
HO OH
OH
O
O
O
O
NH
O
N
HN
H
H
L-Lys-D-Ala-D-Lac
vancomicina de-ossigenata
active on non-mutated form too
HN
O
HN
O
O
repulsione
O
O
convivenza
vancomicina
D-Ala-D-Lac D-Ala-D-Lac
vancomicina de-ossigenata
Vancomycin
vancomycin de-oxygenated vancomycin
repulsion tolerance
de-oxygenated vancomycin
mutation
(N-Ac-L-Lys-D-Ala-D-Lac)
resistance
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Use of boron atoms in Medicinal Chemistry
Boron compounds
• estrogenic ligands
• antitumor agents
• antifungal agents
• antiviral agents
• antimalaric agents
• BNCT
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Similarities between C=C and B-N
Chemistry & Biology 2007, 14, 659-669.
Estrogenic ligands
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Antitumor drugs in clinical use
Nature Chem. Biol. 2006, 2, 689-700.
CML = chronic myelogenous leukemia
GIST = gastro-intestinal stromal tumor
N
N
N
O
H
NH
O BOHHO
BORTEZOMIB
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Boronic acids in Medicinal Chemistry
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Antitumor agents
• inhibitors of tubulin polymerization
Boronic acids in Medicinal Chemistry
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Antitumor agents
• proteasome inhibitors
N
N
N
O
H
NH
O BOHHO
BORTEZOMIB
Boronic acids in Medicinal Chemistry
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Antitumor agents
• histone deacetylase (HDAC) inhibitors
Boronic acids in Medicinal Chemistry
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Antitumor agents
• steroid-sulfatase (STS) inhibitors
26: competitive inhibitor (Ki = 2.8 M)
27a,b: non-competitive inhibitors (Ki = 250 nM, both)
Boronic acids in Medicinal Chemistry
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Antitumor agents
• EGFR tyrosine kinase inhibitors
Erlotinib
(Tarceva)
Boronic acids in Medicinal Chemistry
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Antitumor agents
• Hypoxia-Inducible-Factor 1 alpha (HIF-1 ) inhibitors
Boronic acids in Medicinal Chemistry
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Boron-containing antifungal agents
Science 2007, 316, 1759-1761.
J. Med. Chem. 2006, 49, 4447-4450.
Onychomycosis: caused by some types of dermatophytes, inparticular by
Trichophyton rubrum and Trichophyton mentagrophytes
MIC varying from 0.25 M to 1 M
inactive analogues
6-member ring emiacetal lactone
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Science 2007, 316, 1759-1761.
J. Med. Chem. 2006, 49, 4447-4450.
target: one of the amminoacil – transfer-RNA synthetase (AARS), LeuRS.
mechanism of action:
formation of a cyclic boronic ester with cis-1,2-diol of AMP present in the editing site of
LeuRS (X-ray)
Boron-containing antifungal agents
LeuRS
editing site
LeuRS
editing site
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antimalarial agents
Bioorg. Med. Chem. Lett. 2011, 21, 644-651.
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J. Med. Chem. 2011, 54, 1276-1287.
Design, Synthesis, and Structure-Activity
Relationship of Trypanosoma brucei
Leucyl-tRNA Synthetase Inhibitors as
Antitrypanosomal Agents
antitrypanosomal agents
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Boron-containing antibacterial agents
insensible to -lactamases
J. Med. Chem. 2009, 52, 6097-6106.
bacterial transpeptidase: mechanism
carboxy
peptidase
cross-linked
peptide
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J. Med. Chem. 2009, 52, 6097-6106.
bacterial transpeptidase inhibitors: -lactams vs. boronic acids
-lactams
boronic acids
Boron-containing antibacterial agents
insensible to -lactamases
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J. Med. Chem. 2009, 52, 6097-6106.
Boron-containing antibacterial agents
insensible to -lactamases
cavity in the
enzyme
active-site
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Med. Chem. Comm. 2011, 2, 390-395.
Study of the mechanism of inibition (11B-NMR)
model enzyme: a serine-protease ( -chymotrypsin, CT)
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Compound in pre-clinical development (dermatological infections)
Boron-containing antibacterial agents
insensible to -lactamases
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Anti-hepatitis C agents: inhibitors of HCV-NS3 protease
Bioorg. Med. Chem. Lett. 2009, 19, 180-183.
Ki = 14 nM Ki = 0.2 nM
-ketoamide boronic acid
boronic inhibitor
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Anti-hepatitis C agents: inhibitors of HCV-NS3 protease
Bioorg. Med. Chem. Lett. 2009, 19, 180-183.
Ki = 14 nM Ki = 0.2 nM
-ketoamide boronic acid
boronic inhibitor
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Boron Neutron Capture Therapy (BNCT)
http://web.mit.edu/
-Particles destroy hypoxic cells too (≠ -rays, which need O2)
Minimum efficient concentration: 20 g di 10B per gram of tumor (0.002%)
active isotope (10B): 20% (11B, 80%, inactive)
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4-Borono-L-phenylalanine
Radiother. Oncol. 1993, 27, 46-54.
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carboranes
very stable structures (aromaticity, Huckel rule)
high density of boron atoms (however, 10B: 20%)
B B
BB
B
B
B
B
B
B
B B
B
C
B
B
B
B
B
B
B
CH
H
H
H
R'
RR'R
o-carborano
synthesis
o-carborane
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carboranes
very stable structures (aromaticity, Huckel rule)
high density of boron atoms (however, 10B: 20%)
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“enriched” carboranes
J. Am. Chem. Soc. 2007, 129, 6507-6512
catalytic enrichment reaction with [10B]-diborane
enrichment
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conjugated carboranes
Coord. Chem. Rev. 2002, 232, 173-230.
high uptake of sugars (especially Glu) in tumors
carboranes conjugated with glucose (18), lactose (16) e maltose (17)
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carboranic analog of aspirin
lipophilicity
cell membrane permeability
ChemMedChem 2009, 7, 746-748.
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Complexity, pharmacoforic elements, synthesis
Acc. Chem. Res. 2008, 41, 40-49.
FOS = function oriented synthesis
FOS = function
oriented
synthesis
natural
antimalarial
agent
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FOS = function
oriented
synthesis
activation by means of a Bergman cyclization (irradiation or pH):
DNA break
Acc. Chem. Res. 2008, 41, 40-49.
Complexity, pharmacoforic elements, synthesis
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FOS = function
oriented
synthesis
microtubule destabilization:
anti-neoplastic activity.
Acc. Chem. Res. 2008, 41, 40-49.
Complexity, pharmacoforic elements, synthesis
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FOS = function
oriented
synthesis
antilipemic
Acc. Chem. Res. 2008, 41, 40-49.
Complexity, pharmacoforic elements, synthesis
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FOS = function
oriented
synthesis
antibacterial
J.Med. Chem. 2010, 53, 3793–3813
Complexity, pharmacoforic elements, synthesis
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Drug likeness
Launch,
Marketing
etc.
Manufac-
turing
Clinical
Phase III
Clinical
Phase II
FTIH
To
PoC
Candidate
to Clinical
Candidate
Lead to
Candidate
Hit to
Lead
Screen
to Hit
Target to
Validated
Target
Gene to
Function
Hit: dose-dependent good activity in
preliminary screening
Candidate: efficacy and safety in vivo,
large-scale economic synthesis
Lead: satisfactory potency and selectivity;
suitable physico-chemical and
pharmacokinetic properties; lack of toxicity
Drug development process
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Drug likeness
• higher chances of success
• reduced times of the development phase
• reduced costs of the development phase
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1) privileged structures
2) ADME-Tox
Drug likeness
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1) privileged structures
C. G. Wermuth “The Practice of Medicinal Chemistry”, 2nd Edition,
Elsevier – Academic Press, London, UK, 2003. [ISBN 0-12-744481-5]
Pag.151, Fig.10.3.
A
A
diphenylmethane
N
spiropiperidine
N
NN
N
biphenyltetrazole
N
N
O
benzodiazepine
NO
benzazepine
O
2,2-dimethylbenzopyran.
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J. Med. Chem. 1996, 39, 2887-2893.
1) privileged structures
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ChemMedChem 2007, 2, 861-873.
1 bis) non-desired structures
sub-structures present in drugs causing arrhythmia
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Nature 2007, 448, 645-646.
1 tris) “consolidated” structured
9990 drugs available
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J. Med. Chem. 2008, 51, 1214-1222.
1) “kinase likeness” – privileged structures for kinase inhibitors
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J. Med. Chem. 2008, 51, 1214-1222.
1) “kinase likeness” – privileged structures for kinase inhibitors
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J. Med. Chem. 2008, 51, 1214-1222.
1) “kinase likeness” – privileged structures for kinase inhibitors
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J. Med. Chem. 2008, 51, 1214-1222.
“2-0 rule” + bisarylaniline structure
1) “kinase likeness” – privileged structures for kinase inhibitors
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J. Med. Chem. 2010, 53, 1413-1437.
Kinase ATP-site
1) “kinase likeness” – privileged structures for kinase inhibitors
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Drug likeness
ADMET considerations
A = absorption
D = distribution
M = metabolism
E = excretion
Tox = toxicity
in the early stages of drug-discovery
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ADMET
ChemMedChem 2006, 1, 920-937.
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Drug likeness
ADMET considerations
A = absorption
D = distribution
M = metabolism
E = excretion
Tox = toxicity
in the early stages of drug-discovery
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Toxicity predictions
Drug. Discovery Today 1997, 2, 382-384.
Chemically reactive groups:
NO!
Drug likeness
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toxicity Case of rofecoxib (COX-2 inhibitor)
Tetrahedron Lett. 2005, 46, 927-929.
OO
H
H
SO2CH3
N
N
SO2NH2
CF3
H3C
NO
SO2NH2
CH3
1, rofecoxib 2, celecoxib 3, valdecoxib
OO
H
H
ArPh
OHO
ArPh
H OO
ArPh
H ODO
ArPh
H OO
D
H
ArPh
OO
D
D
ArPh-H
+D2O
A B C D E F
4
OO H
SO2CH3
O2
(aria)
OO
SO2CH3
OH OO
SO2CH3
O
+
5 6
H2O
Ar
COOHHOOC
Ph
Nu- Ar
COOH
Ph
Nu
O
7
8