Isosteres in Medicinal Chemistry
Christos Mitsos
Reviews
G. A Patani, E. J. LaVoie, Chem Rev. 1996, 3147-3176.
C. G. Wermuth, in The Practice of Medicinal Chemistry,
Academic Press 1996, pp 203-237.
Group Meeting
2/1/2006
Definition of Bioisosterism
Friedman (1951): Bioisosteres are atoms or molecules that fit
the broadest definition for isosteres and have the same type of
biological activity.
Definition of Isosterism
Langmuir (1919): Compounds or groups of atoms having the
same number of atoms and electrons
Thornber (1979): Groups or molecules which have chemical and
physical similarities producing broadly similar biological effects.
Examples: N2 and CO, N2O and CO2, N3- and NCOGrimm (1925): “Hydride Displacement Law” addition of
hydride to an atom gives to the resulting pseudoatom' the
properties of the atom with the next highest atomic number.
Parameters affected with bioisosteric replacements
Size, conformation, inductive and mesomeric effects,
polarizability, H-bond formation capacity, pKa, solubility,
hydrophobicity, reactivity, stability.
Hydride Displacement Law
C
N
O
F
Ne
Na+
CH
NH
OH
FH
-
CH2
NH2
OH2
FH2+
• Less side effects
CH3
NH3
OH3+
• Decreased toxicity
CH4
NH4+
• Improved pharmacokinetics (solubility-hydrophobicity)
Bioisosteric replacements: Why?
• Greater selectivity
• Increased stability
Erlenmeyer (1932): atoms, ions or molecules in which the
peripheral layers of electrons can be consider identical.
Examples: atoms in the same column of the periodic table, Cl
and CN and SCN (despite having different number of atoms)
• Simplified synthesis
•Patented lead compounds
Group Meeting
2/1/2006
Isosteres in Medicinal Chemistry
Christos Mitsos
O
OH
H to F replacement
HN
Fluorine: similar size with hydrogen
most electronegative halogen
C-F bond very stable
H
F
Cl
O
CH3
CF3
2
2
Molecular
Refractivity
1.03
0.92
6.03
5.65
5.02
Inductive
effect
-
3.08
2.68
0.00
2.85
1.80
F
HN
1.2
1.35
O
O
Van der
Waals radius
Resonance
effect
F
O
-O
P
-O O
N
R
E-SH
S
HN
E
O
N
R
2'-deoxyuridylic
N
E-SH
O
O
OH
OH
CH3
HN
HN
N
R
Thymidylate
(DNA synthesis)
O
5-Fluorouracil
(antineoplastic)
O
N
R
E-SH: Thymidylate synthase
F
0.00
-0.34
-0.15
-0.13
0.19
O
Ideal replacement to study the effect of electronegativity change
without affecting steric requirements
N
NHMe
N
F3C
F
Flunarizin
(Sibelium)
Ca channel blocker
Fluoxetine
(Prozac)
antidepreessant
F (or other halogens) can be placed on eacily oxidized positions
to increase stability during metabolic processes
O
F
F
Thus, F (or other halogens when size is not critical) are
frequently place on easily oxidized aromatics
Methyl groups often substituted by CF3
CO2H
OAc
Flufenisal
analgesis
N
CO2H
N
HN
Ciprofloxacin
(Cipro)
antibacterial
S
E
-OH to -NH2 or –SH replacement
(also C=O to C=NH or C=S)
O and NH have similar sizes (but not SH)
All three bear H-bonding donor and acceptor capacities
MeO2C
X
CO2Et
N
N
H
Me
Dihydropyrimidine
calcium channel blockers
H2N
N
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Isosteres in Medicinal Chemistry
Christos Mitsos
X
Van der Waals
radius (Å)
IC50
(nm)
O
1.40
140
NH
1.50
160
S
1.85
17
N
N
H
N
N
Halogen replacements
H
N
X
O
CO2H
CO2H
X = NH2, Aminopterin (Methotrexate)
(an antimetabolite anticancer)
CN and CF3 may be used as alternative electron-withdrawing
groups instead of halogens.
The two groups have comparable effects on electronics, but CN
will increase the overall hydrophilicity.
X = OH, Folic acid
Replacement of OH with NH2 can stabilize a different tautomer,
especially in the case of heterocyclic systems
N
H
O
N
Ring replacements
Sulfonamide antebacterials: phenyl group may be replaced by
many heterocycclic aromatics to give active compounds
O O
S
Ar
N
H
OH
more stable
N
Ar =
N
H2N
Sulfapyridine
N
H
NH
N
Sulfapyrazine
S
N
NH2
more stable
N
N
Sulfathiazole
N
Sulfapyrimidine
COOH replacements
Peptide surrogates
O
O
O
N
H
OH
OH
N
H
CN
acylcyanamide
hydroxamic
(strong chelating
agents)
O O O
S
N
R
H
sulfonimide
Peptides are characterized by diminished bioavailability
when administered orally.
Replacement of the sensitive amide bond by various groups
can increase their stability.
(similar acidities)
O
P OH
OH
O O
S
OH
O O
S
NHR
phosphonate
sulfonate
(more acidic;
ionized at physiological pH)
sulfonamide
N N
N
N
H
O N
H
N
(less acidic)
O
O
hydroxyisoxazole
N
R
R1
Ester
N
H
O
O
N-alkylation
R2
H
N
H
N
oxadiazolone
Carboxyl group may be replaced in order to alter acidity, or modify
lipophilicity without affecting pKa
Tetrazoles have comparable pK’s with carboxylic acids, but greater
lipophilicity
O
R1
N
Losartan
(antihypypertensive)
N
H
H
N
O
R1
R2
O
N
H
N
O
Azapeptide
H
N
R2
S
N
H
Thioamide
N
R2
O
Amide to double bond
R1
Cl
CH3
R2
O
H
N
R1
R1
N N
HN
N
R2
O
N O
OH
tetrazole
HO
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2/1/2006
Isosteres in Medicinal Chemistry
Christos Mitsos
H
N
O
R1
R2
O
N
H
O
Dehydroaminoacid
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2/1/2006
Isosteres in Medicinal Chemistry
Christos Mitsos
Preparation of tetrazoles
BocHN
Ph
R
N
R
R
N
BocHN
N
HN N
base, ∆
N
N N
CN
N
Ph
PPh3, THF
Ph3P
O
Ph
CN
N
BocHN
NaOH;
Ph
N
N N
HCl
N
N
HN N
NJ. Med. Chem 2000, 43, 488.
N N
N
CN
N
H
NaN3, NH4Cl
PhtHN
DMF, 90 oC
CO2Me
CN
N
HN3
R
TMSN3, DEAD
O
N
-N N
BocHN
H
N
PhtHN
MeO
ClCH2C(OEt)3
NH2
NaN3, AcOH
Cl
Cl
EtO
N
PMB
PMB
N
N
N N
CO2Me
Tet Lett 1998, 39, 3367.
O
O
HN
CO2H
N
H
O
NH2
MeCN, reflux
N
N
N
NH
N N
N
SiR3
H2O
Tomudex analogues
J. Med. Chem. 1999, 42, 3809.
N N
N
N
SiR3
OSiR3
SiCl4, NaN3
Tet Lett 1997, 38, 1257.
N N
N
N
H
Group Meeting
2/1/2006
Isosteres in Medicinal Chemistry
Christos Mitsos
Peptide (amide) repalcements
Amide to alpha-difluoroketone
Amide to hydroxyethyl
O
H
N
BocHN
O
N
H
Me
Me
BocHN
HO
O
1. BF3.OEt2, EtOH
2. MeOH, KOH
3. PivCl
OHC
OAc
4. TBSCl
5. LAH
6. [O]
OAc
AcO
O
OEt
CbzHN
N
H
Me
Me
O
Chx
1. ChxCHPPh3
2. Jone's
3. H2, Pd-C
O
O
COOMe
Ph
O
i-Bu
1. H2, Rh-C
2. TMSCN
3. DIBAL
CHO
Chx
CF2Br2, HMPT
i-Bu
Chx
MeOH, H+
Me
LHMDS2, -90 °C;
TBSCl, rt; H3O+
F F
Chx
COOH
i-Bu
i-Bu
O
HO
50 : 50
CF2
O
Chx
O
Me
O
Me
Me
O
1. (COCl)2
2. NH3
3. Et3OBF4
NH
F F
Chx
OEt
I2, NaHCO3,
radical scavenger
OEt
equilibrate with LHMDS
i-Bu
N
F
Chx
i-Bu
I
Chx
1. DEAD, DPPA
2. H2, Pd-C
H2N
Me
O
1. RCOOH,
DPPCN
2. n-BuNH2
Chx
RCOHN
Me
O
NHn-Bu
HO
O
CF2
OTMS
Chx
OTMS
1. NaOH
2. n-BuLi,
ClCOCH2-i-Bu
TBSO
COOEt
CbzHN
TBSO
TBSO
O
F F
COOEt
OH
Chx
1. LiNTMS2, MeCHO
2. MsCl
3. Me2CuLi
H
N
O
Me
Me
Shiozaki, et.al. Tetrahedron Lett. 1989, 30, 3669-3670.
1. H3O+
2. CbzCl
3. PTFA
Chx
F F
Moffatt
Chx
COOEt
CbzHN
OH
i-Bu
F
F F
COOEt
(78%) CbzHN
O
i-Bu
Damon, D. B.; Hoover, D. J. J. Am. Chem. Soc. 1990, 112, 6439-6442.
Group Meeting
2/1/2006
Isosteres in Medicinal Chemistry
Christos Mitsos
Peptide (amide) repalcements
Amide to alkene
Amide to alkene
Me
BnO
BnO
H
N
CbzHN
COOH
Me
COOH
CbzHN
H
N
BocHN
O
O
CONH2
CONH2
1. ClCOOEt, NaBH4
2. Bu3P, (PhS)2
3. MCPBA
OBn
CbzHN
Me
OBn
COOH
Me
CbzHN
1. LDA, ICH2COO-i-Bu
2. LAH
O
Me
Aux
OHC
CO2-t-Bu
CO2H
CO2-t-Bu
Me
CbzHN
CbzHN
CbzHN
SO2Ph +
OTHP
CO2-t-Bu
CO2Et
Me
1. NaOH
2. DCC, t-BuOH
3. (Boc)2O
OBn
OHC
1. DIBAL
2. CH3C(OMe)3
Me
Me
CO2-t-Bu
Me
OBn
1. MeLi
MeOAl(i-Bu)2
Me
Cbz
CbzHN
OTHP
CO2-t-Bu
Me
EDCI,
PheNH2
Me
OBn
Jones'
CbzHN
CbzHN
OH
CONH2
CO2-t-Bu
COOMe
2. Na(Hg),
NaH2PO4
OBn
1. OsO4, NMO
2. NaIO4
3. Jones'
4. NaOH
N
Boc
Me
1. TFA
2. NH3
Phe-NH2
OTHP
3. DHP
4. O3; DMS
Me
O
BocHN
Phe-NH2
1. DCC, 3,5diMe-pyrazole
2. LAH
3. HWE
Me
SO2Ph
CbzHN
Me
O
BocHN
COOH
CONH2
de Gaeta, et.al. J. Org. Chem. 1989, 54, 4004-4005.
Spaltenstein, et.al. J. Org. Chem. 1987, 52, 3759-3766.
Me
CO2H
BocHN
CO2-t-Bu
O
PheNH2
CO2-t-Bu
Separate by Flash Chromatography
Shue, et.al. Tetrahedron Lett. 1988, 29, 4041-4044.