Pharmacy_Lecture_08_..

Dr. P. Wipf
Page 43 of 64
Bioisosterism
Bioisosteres - substituents or groups with
chemical or physical similarities that
produce similar biological properties.
Can attenuate toxicity, modify activity of
lead, and/or alter pharmacokinetics of
lead.
2/14/2008
Dr. P. Wipf
Page 44 of 64
Bioisosterism allows modification
of physicochemical parameters
Multiple alterations may be necessary:
If a bioisosteric modification for receptor
binding decreases lipophilicity, you may
have to modify a different part of the
molecule with a lipophilic group.
Where on the molecule do you go to
make the modification?
2/14/2008
Dr. P. Wipf
Page 45 of 64
2/14/2008
1. Univalent atoms and groups
a. CH3
b. Cl
c. Br
d. I
Classical Isosteres
NH2 OH F Cl
PH2 SH
i-Pr
t-Bu
2. Bivalent atoms and groups
a.
b.
CH2
COCH2R
NH
O
Se
S
CONHR
CO2R
COSR
3. Trivalent atoms and groups
a.
CH
N
b.
P
As
4. Tetravalent atoms
a.
b.
C
C
Si
N
P
5. Ring equivalents
a.
CH CH
S
(e.g., benzene, thiophene)
(e.g., benzene, pyridine)
b.
CH
N
c.
O
S
CH2
NH
(e.g., tetrahydrofuran,
tetrahydrothiophene,
cyclopentane, pyrrolidine)
Dr. P. Wipf
NonClassical
Isosteres
Do not have the
same number of
atoms and do not
fit steric and
electronic rules of
classical isosteres,
but have similar
biological activity.
Page 46 of 64
2/14/2008
1. Carbonyl group
NC
O
C
CN
O
S
C
O
CN
O
NOCH3
C
NOH
C
CN
CH
S
O
S
N
O
R
O
2. Carboxylic acid group
O
C
O
S N H
O R
OH
O
N
H
O
S
N
OH
N
N
OH
O
X
O
O
OH
OH
O
F
OH
N
N OH
OH
N
N
F
3. Amide group
O
C
HN
NH2
O
C
O
HN
O
C
O
C
OR
S
C
HN
NH2
O
S
O
C
OH
CH2
N
O
N N
N
N
H
OH
NH
OH
N
N N
O
O
S
S
N
Ar
O H O
O
S
N
Ar
O
H
CH3
N
N
O
O
C NH
CN
O
P OH
OEt
O
O
S
N
Ar
O
H
N
N
OH
O
P OH
NH2
O
S OH
O
CH3
NH2
CH2
H2C
HN
O
C
N
NH2
NH2
Dr. P. Wipf
Page 47 of 64
2/14/2008
4. Ester group
O
C
OR
N O
N
O
S
NRR'
ON S
OR
O
C
R'
N
F
N
R
OR
N
N
S
R'
N
N
N
N
R'
N N
N
S
O
R'
N
N
N
N
O N
OR
OR
5. Hydroxyl group
O
NHCR
OH
NHSO2R
NHCR
O
NHCNH2
CH2OH
CH(CN)2
6. Catechol
HO
H
N
O
HO
N
HO
O
S
O
X
HO
HN
N
X = O, NR
HO
7. Halogen
X
CF3
CN
N(CN)2
C(CN)3
8. Thioether
S
O
NC
CN
CN
N
9. Thiourea
S
HN
N
NH2
HN
CN
NH2
NO2
HN
NH2
N
SO2NH2
NH2
R'
Dr. P. Wipf
Page 48 of 64
2/14/2008
10. Azomethine
CN
C
N
11. Pyridine
N+
R
N
NO2
NR3
12. Benzene
N
N
S
S
O
O
O
H
N
N
N
N
N
N
13. Ring equivalents
R
R
N
R
14. Spacer group
(CH2)3
15. Hydrogen
H
F
O
R'
H3C
R
N
O
R'
O
H
O
N
R
O
R
H
N
N
H
NH2
Dr. P. Wipf
Page 49 of 64
2/14/2008
Examples of Bioisosteric Analogues
Neuroleptics (antipsychotics)
Anti-inflammatory agents
X
N
(CH2)3 X
N
H
O
CH3
CH3O
R
X = OH (indomethacin)
= NHOH
N N
=
N
N
H
N
X=
O
C
O
or CHCN
Cl
OH
Y
O
CH3
Y=F
Antihistamines
R X (CH2)n Y
Y = CH3O Z = Cl
Z
X = NH, O, CH2
Y = N(CH3)2 (n = 2)
N
(n = 1)
N
H
Ph
Ph
CO2H
O
N
NH
(n = 1, 2)
N
Z = SCH3 (sulindac)
Diphenhydramine
(Benadryl)
Ph
HO
Ph
N
OH
Fexofenadine
(Allegra)
Dr. P. Wipf
Page 50 of 64
Changes resulting from bioisosteric replacements:
Effects of bioisosteric replacement:
2/14/2008
Dr. P. Wipf
Page 51 of 64
Rational Drug Discovery
2/14/2008
Dr. P. Wipf
Page 52 of 64
2/14/2008
Structure-Activity Relationships
(SARs)
1868 - Crum-Brown and Fraser
Examined neuromuscular blocking effects of
a variety of simple quaternary ammonium
salts to determine if the quaternary amine in
curare was the cause for its muscle paralytic
properties.
Conclusion: the physiological action is a
function of chemical constitution
Dr. P. Wipf
Page 53 of 64
Structurally specific drugs (most drugs):
Structurally nonspecific drugs:
2/14/2008
Dr. P. Wipf
Page 54 of 64
2/14/2008
Example of SAR
H2N
SO2NHR
sulfa drugs
2.1
Lead: sulfanilamide (R = H)
Thousands of analogs synthesized
From clinical trials, various analogs shown
to possess three different activities:
• Antimicrobial
• Diuretic
• Antidiabetic
Dr. P. Wipf
Page 55 of 64
2/14/2008
SAR
General Structure of Antimicrobial Agents
NH 2
R
2.32
R = SO2NHR′, SO3H
• Groups must be para
• Must be NH2 (or converted to NH2 in vivo)
• Replacement of benzene ring or added substituents
decreases or abolishes activity
• R can be
SO2
NH 2
,
SO
NH 2
,
O
CNH2
(but potency is reduced)
• R = SO2NR′2 gives inactive compounds
O
,
C
R
Dr. P. Wipf
Page 56 of 64
2/14/2008
A schematic representation of drugs that originated from sulfanilamide. A single chemical motif
gave rise to antibiotics, hypoglycemic agents, diuretics, and antihypertensive drugs.
Drews, J., "Drug discovery: A historical perspective." Science 2000, 287, 1960-1964.
Dr. P. Wipf
Page 57 of 64
2/14/2008
Rational Drug Discovery - Piroxicam
• It took Pfizer ~18 years to develop the anti-inflammatory drug piroxicam,
which was launched in 1980 during the “golden age of rational drug
discovery”.
• The starting point for the development was chemistry-driven, I.e. to identify
acidic, but not carboxylic acid-containing (salicylic acid) structurally novel
compounds.
• Measurement of a physical property (pKa) as well as serum half-life in
dogs was the guide for the synthesis program.
• Several generations of leads were refined and ultimately led to a
successful structure with an acceptable safety and activity profile:
Dr. P. Wipf
Page 58 of 64
Structure-Based Design of Potent Non-Peptide
MDM2 inhibitors
The pharmacological
hypothesis:
The p53 tumor suppressor plays a
central role in controlling cell cycle
progression and apoptosis, and it is
an attractive cancer therapeutic
target because its stimulation kills
tumor cells.
Its low intracellular concentration is
maintained by MDM2-mediated
ubiquitination and resulting
proteolysis.
An approach toward stimulation of
p53 activity would be to block its
interaction with the MDM2
oncoprotein.
Ding et al. JACS 2005, 127, 10130.
2/14/2008
Dr. P. Wipf
Page 59 of 64
2/14/2008
Structure-Based Design of Potent Non-Peptide
MDM2 inhibitors
Structure-Based
Design:
The p53-MDM2 interaction is
primarily mediated by three
hydrophobic residues of p53 and a
small but deep hydrophobic cleft in
MDM2. This cleft is ideal for the
design of agents that block the p53MDM2 interaction.
Trp23 appears to be buried most
deeply in the hydrophobic cavity,
and its NH group forms a hydrogen
bond with a backbone carbonyl in
MDM2. Indeed, imidazolines were
previously reported to inhibit
MDM2 (“Nutlins”).
What other chemical moieties can
mimic the indole ring?
Phe19
MDM2
Trp23
Leu26
Dr. P. Wipf
Page 60 of 64
Structure-Based Design of Potent Non-Peptide
MDM2 inhibitors
Structure-Based Strategy:
1.
2.
The oxindole is a bioisostere of the indole.
Identify natural products that contain an oxindole substructure.
3.
Although spirotryprostatin and alstonisine fit poorly into the MDM2 cavity, the spiro-oxindolepyrrolidine core structure fit well.
Two additional hydrophobic groups are needed to mimic the side chains of Phe19 and Leu26.
Candidates were evaluated by molecular modeling & docking.
4.
2/14/2008
Dr. P. Wipf
Page 61 of 64
2/14/2008
Structure-Based Design of Potent Non-Peptide
MDM2 inhibitors
Structure-Based Strategy:
1.
2.
3.
4.
5.
The initial lead compound was synthesized by an asymmetric 1,3-dipolar cycloaddition.
Biological analyses vs a fluorescent-labeled p53-based peptide (Kd 1 nM) provided a Kd of 9 uM for
the lead compound.
How could further optimization be performed?
Additional room in the MDM2 cavity could be exploited by larger hydrophobic groups (supported by
modeling studies).
After several rounds of SAR, where the modeling was tested both by the synthesis of supposedly
improved as well as inferior molecules, a new compound with Kd 86 nM was identified.
Dr. P. Wipf
Page 62 of 64
2/14/2008
Structure-Based Design of Potent Non-Peptide
MDM2 inhibitors
Structure-Based Strategy:
1.
Predicted binding model using computational docking for initial lead compound and for the
optimized compound 1d.
Cl
O
O
N
R2
NH
R3
R1
O
N
H
Spiro-oxindole core structure
2.
Structure-based
design of
initial lead
(R)
NH
(R) (R)
(S)
Cl
(R)
Structure-based
optimization
Initial lead compound
What are the potential issues with MDM2 inhibitors?
NH
(R) (R)
(S)
O
N
H
N
Cl
O
N
H
Potent inhibitor
Dr. P. Wipf
Page 63 of 64
2/14/2008
Structure-Based Design of Potent Non-Peptide
MDM2 inhibitors
O
Substructure
search
HN
O
HN
Substructure
search
HN
O H O
N
H
HN
O
Trp23 in p53
Oxindole core structure
R2
NH
R3
R1
O
N
H
Spiro-oxindole core structure
Structure-based
design of
initial lead
N
Alstonisine
Cl
N
(R)
NH
(R) (R)
(S)
Cl
H
O
H
Spirotryprostatin A
O
Structure-based
selection
of core structure
O
Initial lead compound
O
N
(R)
Structure-based
optimization
NH
(R) (R)
(S)
O
N
H
H
NH
N
O
O
H
Cl
O
N
H
Potent inhibitor
Dr. P. Wipf
Page 64 of 64
2/14/2008
Assigned Reading (i.e. your homework!):
Drews, J., "Case histories, magic bullets and the state of drug discovery."
Nat. Rev. Drug Discovery 2006, 5, 635-640.