Paruch Medicinal Chemistry C9115Bioisosteres
Bioisostere
both classical and non-classical isosteres
a group that can be used to replace another group while retaining the desired biological
activity
often used to replace a functional group that is important for target binding, but is
problematic in one way or another (e.g. Toxicity)
replacing a functional group with a bioisostere is NOT guaranteed to retain activity for every
drug at every target
In some situations, the use of a bioisostere can actually increase target interactions and/or
selectivity
Classical isosteres Non-classical isosteres
Paruch Medicinal Chemistry C9115Bioisosteres
The results of bioisosteric replacement
1) Structural: conformation; size; bond angle
Scaffold hopping can be seen as an example
2) Receptor interactions: most relevant parameters will be size, shape, electronic properties, pKa,
chemical reactivity, and hydrogen bonding.
3) Pharmacokinetics: optimization of absorption, transport, and excretion properties of the molecule
the most important parameters to consider are lipophilicity, hydrophilicity, hydrogen bonding, pKa
4) Metabolism: Chemical reactivity is an important property to optimize
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of Hydrogen by Deuterium
• minor impact on the physicochemical properties
• usually introduced to modulate metabolism
• If the bond to the H being replaced is broken
during the rate-determining step – Kinetic
isotopic effect
• Slow epimerization
Tetrabenazine (treatment of Huntington’s Disease–
Related Chorea) is well absorbed but it has relatively
low bioavailability and the primary route for
metabolism is via oxidation by CYP2D6.
Deutetrabenazine from Teva - the half-life nearly
twice that of tetrabenazine, allowing it to be
administered twice rather than three times a day, and
at lower doses, thus reducing peak concentration
adverse effects while maintaining efficacy.
https://www.cambridgemedchemconsulting.com/resources/bioisoteres/
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of Hydrogen by Fluorine
Fluorine
• introduced to reduce basicity of proximal amines or increase acidity of proximal acids
• to introduce a conformational bias in molecules
• C-F bond is strong and thus resistant to metabolic cleavage
• is highly electron-withdrawing - serves to reduce the potential for oxidative metabolism
Review: K.L. Kirk Current Topics in Medicinal Chemistry, 2006, 6 (14), 1447
Fluorine as a bioisotere of H: N.A. Meanwell J. Med. Chem. 2018, 61, 5822
Paruch Medicinal Chemistry C9115Bioisosteres
The strategic deployment of a fluorine atom to modulate basicity was probed in
the context of inhibitors of kinesin spindle protein (KSP)
N. A. Meanwell J. Med. Chem. 2011, 54, 2529–2591
23 was dealkylated in rat liver
microsomes (RLM) as the major
metabolic pathway to afford 24 and
fluoroacetaldehyde, which was
oxidized to fluoroacetic acid, a
highly toxic substance
F substituent in the piperidine ring where the effect
on pKa was dependent on stereochemical disposition.
In the trans analogue 26, the F in equatorial position
- reduction in basicity from pKa = 8.8 to pKa = 6.6.
In contrast, in the cis isomer 25, the F is disposed
axially, effect on basicity - pKa = 7.6. This
compound, MK-0731 (25), was subsequently advanced
into clinical trials.
Paruch Medicinal Chemistry C9115Bioisosteres
Effect:
• Enhancing potency
• Reducing polarity
• Increasing lipophilicity (improve membrane permeability)
• Enhancing pharmacokinetic properties
• Reducing the potential for toxicity
Carboxylic acid isosteres
N. A. Meanwell J. Med. Chem. 2011, 54, 2529–2591
Paruch Medicinal Chemistry C9115Bioisosteres
Carboxylic acid isosteres
N. A. Meanwell J. Med. Chem. 2011, 54, 2529–2591
Paruch Medicinal Chemistry C9115Bioisosteres
Carboxylic acid isosteres
Aldose reductase inhibitors (Diabetes)
N. A. Meanwell J. Med. Chem. 2011, 54, 2529–2591
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement phenol or catechol
N. A. Meanwell J. Med. Chem. 2011, 54, 2529–2591
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of amides and esters
C.R.J. Stephenson et al. ACS Med. Chem. Lett. 2020, 11, 10, 1785–1788
Amide isosteres - modulating polarity and bioavailability
Ester isosteres - address metabolism issues (esters can be rapidly cleaved in vivo)
Paruch Medicinal Chemistry C9115Bioisosteres
The trifluoroethylamine can act as an isostere of an amide moiety in peptide-based molecules.
• Reducing the basicity of the amine without compromising of the NH to function as a H-bond donor
• CF3CH(R)NHR’ bond is close to 120o observed with an amide
• C-CF3 bond is as polar as C=O bond
Replacement of amides and esters
Cathepsin K inhibitor (Osteoporosis)
C.R.J. Stephenson et al. ACS Med. Chem. Lett. 2020, 11, 10, 1785–1788
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of carbonyl
Simple ketones and aldehydes - typically low prevalence in drugs because of their potential
chemical reactivity (e.g. reduction/oxidation)
N. A. Meanwell J. Med. Chem. 2011, 54, 2529–2591
K. Vandyck et al. J. Med. Chem. 2009, 52, 4099–4102 G. M. Dubowchik et al. Org. Lett. 2001, 3, 3987–3990
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of aniline
C.R.J. Stephenson et al. ACS Med. Chem. Lett. 2020, 11, 10, 1785–1788
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of piperazine
https://enamine.net/download/MedChem/Enamine_Piperazine-Bioisosteres-2019.pdf
P.H. Mykhailiuk et al Angew. Chem. Int. Ed. 2020, 59, 7161 –7167
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of para-substituted benzene
https://enamine.net/download/MedChem/Enamine-Water-Soluble-benzene-mimics-2020.pdf
P.H. Mykhailiuk et al Angew. Chem. Int. Ed. 2020, 59, 7161 –7167
Paruch Medicinal Chemistry C9115Bioisosteres
Replacement of ortho-substituted benzene
https://enamine.net/download/MedChem/Enamine_Saturated_Bioisosteres_of_o-benzene-2020.pdf
P.H. Mykhailiuk et al Angew. Chem. Int. Ed. 2020, 59, 20515 – 20521
Paruch Medicinal Chemistry C9115Bioisosteres
Paruch Medicinal Chemistry C9115Bioisosteres
Bioisostere web database
http://www.swissbioisostere.ch
Paruch Medicinal Chemistry C9115Scaffold hopping
• Scaffold hopping is a strategy for discovering structurally novel compounds
• starts with known active compounds and end with a novel chemotype by
modifying the central core structure of the molecule
• computer-aided search for active compounds containing different core
structures
• can also be attempted on a case-by-case basis from a chemical viewpoint
• compounds with different structures but similar activity
• Reasons: circumventing an intellectual property; replacing a chemically complex
natural product; improving pharmacological properties of known actives
Paruch Medicinal Chemistry C9115Scaffold hopping
The concept of scaffold hopping can be applied to structure-based virtual screening
J. Bajorath et al. J. Med. Chem. 2017, 60, 1238−1246
Paruch Medicinal Chemistry C9115Scaffold hopping
Scaffolds are extracted from compounds by removal of all substituents while
retaining ring systems and linker moieties between rings
The Scaffold Tree algorithm - rules how to systematically decompose a scaffold
1. Remove Heterocycles of Size 3 First
2. Do Not Remove Rings with g 12 Atoms if There Are Still Smaller Rings
To Remove
3. Choose the Parent Scaffold Having the Smallest Number of Acyclic
Linker Bonds
4. Retain Bridged Rings, Spiro Rings, and Nonlinear Ring Fusion Patterns
with Preference
5. Bridged Ring Systems Are Retained with Preference over Spiro Ring
Systems
6. Remove Rings of Sizes 3, 5, and 6 First
7. A Fully Aromatic Ring System Must Not Be Dissected in a Way That the
Resulting System Is Not Aromatic Any More
8. Remove Rings with the Least Number of Heteroatoms First
9. If the Number of Heteroatoms Is Equal, the Priority of Heteroatoms to
Retain is N > O > S.
10.Smaller Rings are Removed First
11.For Mixed Aromatic/Nonaromatic Ring Systems, Retain Nonaromatic
Rings with Priority
12.Remove Rings First Where the Linker Is Attached to a Ring Heteroatom
at Either End of the Linker
A. Schuffenhauer et al. J. Chem. Inf. Model. 2007, 47, 47-58
J. Bajorath et al. J. Med. Chem. 2017, 60, 1238−1246
Paruch Medicinal Chemistry C9115Scaffold hopping
Scaffolds are extracted from compounds by removal of all substituents while
retaining ring systems and linker moieties between rings
A. Schuffenhauer et al. J. Chem. Inf. Model. 2007, 47, 47-58
J. Bajorath et al. J. Med. Chem. 2017, 60, 1238−1246
Paruch Medicinal Chemistry C9115Scaffold hopping
Scaffold hopping events are often of different magnitude
Scaffolds might be very similar, e.g. distinguished by a heteroatom in a ring.
Scaffolds might be completely distinct, e.g. consist of different ring systems with different topology
A. Schuffenhauer et al. J. Chem. Inf. Model. 2007, 47, 47-58
J. Bajorath et al. J. Med. Chem. 2017, 60, 1238−1246
very similar
remotely similar
distinct
Detecting compounds that contain distantly related scaffolds but share
similar activity would be considered a meaningful scaffold hopping event.
Structural distance between two
scaffolds is represented by a number
in range 0 – 1 (blue).
Values ≤ 0.34 = similar scaffolds
Values ≥ 0.74 = dissimilar scaffolds
Paruch Medicinal Chemistry C9115Scaffold hopping
Dopamine agonists
• Starting from the natural ligand
• Fenoldopam - structural similarity to dopamine
• Quinpirole - completely novel structure
Adenosine A2a-antagonists
• starting form the natural ligand adenosine (an agonist)
• or the natural product caffeine (a subtype-unselective antagonist)
Inhibitors of CDK2
M. Stahl et al. Drug Discov. Today Technol., 2004, 1 (3), 217-224
Paruch Medicinal Chemistry C9115Scaffold hopping
M. Stahl et al. Drug Discov. Today Technol., 2004, 1 (3), 217-224
Computational approaches
Method Pros Cons Software
Shape
matching
Fast, high success
rate for small or
rigid compounds
Requires
knowledge about
bioactive
conformation
BioSolveIT
www.biosolveit.de
ROCS
www.eyesopen.com
Pharmacophore
searching
Yielding clear
answers, based on a
maximum of
information
Requires knowledge
about bioactive
conformation and
alignment
Catalyst
www.accelrys.com
Unity
www.tripos.com
Fragment
replacement
Can be performed
on 2D or 3D
structure, high
success rate
Calculations might
yield many or no
results depending
on tolerance
CAVEAT
cchem.Berkeley.edu/
pabgrp/index.html
Similarity
searching
Fast and always
applicable
High degree of
uncertainty because
of high abstraction
from chemical
structure
Daylight
Fingerprints
www.daylight.com
Paruch Medicinal Chemistry C9115Scaffold hopping
For more examples see the review: T. W. Moore, et al. RSC Med. Chem., 2020, 11, 18-29
Scaffold hopping for imparting metabolic stability
Replacement of a phenyl substituent with a pyridyl or pyrimidyl substituent
Benzimidazole, imidazole, and imidazopyridine were identified as potential replacements for pyrrole
core—which can generate toxic metabolites
Paruch Medicinal Chemistry C9115Privileged Scaffolds
In 1988, Evans mentioned the term ‘privileged structures’, describing them as simple structural
subunits present in the molecules of several drugs, with distinctive therapeutic uses, or affinities to
several different receptors.
In medicinal chemistry some scaffolds may have privileged characteristics, being recognized
molecularly by distinctive receptors without being important pharmacophores
B. E. Evans et al. J. Med. Chem., 1988, 31, 2235, A. Gumus et al. Bioorg. Med. Chem. Lett. 2021, 49, 128309
pyrazolo[1,5-a]pyrimidine
insomnia insomnia insomnia fungicideanxiolytic
TrkA, TrkB and TrkC inhibitorTrkA, TrkB and TrkC inhibitorCDK inhibitor
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
Examples of Privileged Scaffolds Found Primarily in Drugs
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Examples of Privileged Scaffolds Found Primarily in Drugs
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Examples of Privileged Scaffolds in Natural Products
Paruch Medicinal Chemistry C9115Privileged Scaffolds
B. R. Stockwell et al. Curr. Opin. Chem. Biol. 2010, 14(3), 347–361
Other examples
Paruch Medicinal Chemistry C9115Privileged Scaffolds
Other examples
E. J. Barreiro, Chapter 1:Privileged Scaffolds in Medicinal Chemistry: An Introduction , in Privileged Scaffolds in Medicinal Chemistry: Design,
Synthesis, Evaluation, 2015, pp. 1-15 DOI: 10.1039/9781782622246-00001
Paruch Medicinal Chemistry C9115Privileged Scaffolds
E. J. Barreiro, Chapter 1:Privileged Scaffolds in Medicinal Chemistry: An Introduction , in Privileged Scaffolds in Medicinal Chemistry: Design,
Synthesis, Evaluation, 2015, pp. 1-15 DOI: 10.1039/9781782622246-00001
Other examples
Paruch Medicinal Chemistry C9115
Partially saturated privileged scaffolds
Privileged Scaffolds
D. R. Spring et al Chem. Commun., 2020, 56, 6818-6821
piperazine-based
Zanubrutinib
Bruton's tyrosine
kinase (BTK) inhibitor
Y. Y. Syed et al Drugs 2020, 80, 91–97
D. R. Spring et al ACIE 2016, 55, 12479 –12483
Paruch Medicinal Chemistry C9115partial saturation
COOH has been considered problematic for cell-based activity;
but it is not always the case
Silmitasertib
inhibitor of protein kinase CK2
Odevixibat
reversible, potent, selective inhibitor
of the ileal bile acid transporter
(IBAT)
Ataluren
treatment of Duchenne muscular dystrophy.
Iptacopan
factor B inhibitor