Lecture 2: Isoteres & Bioisosteres

What is the medicinal chemistry strategy?

“Isosteric replacement” (e.g LBDD)

What are isosteres?

Atoms or FGs w/ similar size, 3-D shape, & valence electron configuration that can often substitute for each other w/o drastically altering structure of a molecule

What are bioisosteres?

Chemical groups that can replace another group in a drug while maintaining similar biological activity but potentially improving properties such as drug potency, drug target selectivity, metabolism, toxicity, etc.

What is the main takeaway about isosteres & bioisosteres?

Isosteric replacement & bioisosteric replacement is one of the most powerful strategies in medical chemistry

• Drug optimization of PK &/or PD

What do classical isosteres involve?

• Atoms or FGs w/ similar size & valence

• Main purpose to maintain size & 3-D geometry

What are examples of classical isosteres?

• Univalent isosteres

• Bivalent isosteres

• Trivalent isosteres

• Ring equivalents

What may change w/ classical isosteres?

• Electonics?

• Solubility?

• Sterically?

• Impact PK? PD?

What are many bivalent isosteres?

Hydrolytic enzymes (ease of hydrolysis)

• Peptidases, proteases, esterases, thioesterases

What if a bond is subject to enzymatic hydrolysis/ bond cleavage?

• Decreases duration of action

• No- increases duration of action

• Can address a PK concern

How to use isosteres in drug target ligand-binding site “mapping” &/or pharmacophore determination?

• Time & labor intensive- slow & expensive

• Approach 1: synthesize Isosteric analog, perform pharmacological assay

  • Possible result: better activity? Same? Worse? (SAR)

• Approach 2: synthesize drug target mutant, perform pharmacological assay

What to assume about in vitro assays?

PK not an issue, good for learning about PD

What to assume about in vivo assays?

PK & PD concerns

What are non-classical bioisosteres?

Groups that do NOT follow relatively strict “valence rules” of classical isosteres, but mimic biological behavior & tend to be far more important in modern drug design than classical isosteres

What is the main purpose of non-classical bioisosteres?

Potentially improve…

1. ADME/PK profile

2. Drug stability

3. Binding to drug target (PD)

What is the strategy for improving drug potency?

Create better drug*drug target interactions (PD)

What is the strategy for improving drug target selectivity?

Alter steric or electronic properties to allow better binding to one drug target vs. another drug target (PD)

What is the strategy for improving metabolic stability?

Remove metabolic hotspots to increase duration of action of a drug (PK)

What is the strategy for improving drug solubility?

Add/remove polarity

What is the strategy for improving drug toxicity?

Remove undesirable reactive groups/toxicophores

What is the strategy for improving PK properties?

Tune lipophilicity

What are the 3 most important bioisosteres in medicinal chemistry?

• CA/tetrazole bioisostere

• Hydrogen/fluorine

• Phenyl/pyridine ring

What is losartan?

Angiotensin II Receptor Blocker (ARB)

What are tetrazoles?

Lipophilic CAs

What is the acidity of CAs & tetrazole bioisosteres?

• Both ~4-5

• Maintain similar ionization at physiological pH

What is the ionic interaction w/ receptor of CAs & tetrazole bioisosteres?

• Strong ionic interaction

• Preserves receptor binding (PD)

What is the hydrogen bonding of CAs & tetrazole bioisosteres?

• CAs: H-bond acceptor/donor

• Tetrazole: comparable H-bonding capability

• Maintains key pharmacophore interactions

What is the charge distribution of CAs & tetrazole bioisosteres?

• CAs: limited delocalization of negative charge over 2 O’s

• Tetrazole: delocalized negative charge over all 4 N’s of tetrazole ring

• Increased stability of ionized form

What is the lipophilicity of CAs & tetrazole bioisosteres?

• CAs: lower

• Tetrazole: higher

• Improves membrane permeability (increases oral absorption)

What is the susceptibility to phase II conjugation of CAs & tetrazole bioisosteres?

• CAs: very likely

• Tetrazole: rare!

• Longer duration of action for tetrazole

What is the oral bioavailability of CAs & tetrazole bioisosteres?

• CAs: sometimes limited

• Tetrazole: typically improved

• Better drug-like properties

What is fluoxetine (prozac)?

Selective Serotonin Reuptake Inhibitor (SSRI)

• Must cross BBB

With fluorine/CF3 group, what does the similar steric size to H do?

• Minimal change in molecular geometry

• Maintains proper binding orientation at drug target (SERT)

With fluorine/CF3 group, what does the strong electron-withdrawing effect do?

• Alters electron density of aromatic ring

• Can improve binding interactions w/ SERT (PD)

With fluorine/CF3 group, what does the very strong C-F bond do?

• Resistant to oxidative metabolsim

• Increased metabolic stability (PK)

With fluorine/CF3 group, what does the formation of CF3 group do?

• Increases lipophilicity

• Improved CNS/BBB penetration & oral absorption (PK)

With fluorine/CF3 group, what does the increased molecular stability do?

• Reduced metabolic degradation

• Longer drug half-life & duration of action (PK)

What is the atomic radius of H vs. F?

• H: very small

• F: slightly larger but comparable to H

• Minimal steric change when replacing H

What is the van der Waals radius of H vs. F?

• H: ~1.20 A

• F: ~1.47 A

• Similar size allows bioisosteric replacement

What is the electronegativity of H vs. F?

• H: 2.20

• F: 3.98 (highest in periodic table)

• Fluorine strongly withdraws electron density

What is the bond strength to carbon of H vs. F?

• H: C-H ~ 410 kJ/mol (weaker)

• F: C-F ~ 485 kJ/mol (very strong!)

• C-F bonds resist metabolic oxidation

What can CYP450 do?

• Break weak C-H bond

• NOT break strong C-F bonds!

What is the polarity of bond of H vs. F?

• H: weakly polar

• F: highly polar

• Alters dipole moment & electronics

What is the hydrogen bonding ability of H vs. F?

• H: weakly polar F donor when bound to heteroatoms

• F: very weak H-bond acceptor

• Can influence binding interactions

What is the H bonding ability of H vs. F?

• H: weak donor when bound to heteroatoms

• F: very weak H-bond acceptor

• Can influence binding interactions

What is the lipophilicity effect of H vs. F?

• H: neutral

• F: often increases lipophilicity when part of CF3 groups

• Improves membrane permeability

What is the metabolic stability of H vs. F?

• H: easily oxidized

• F: highly resistant to oxidative metabolism

• Used to block metabolic “hot spots”!

What is the prevalence in drugs of H vs. F?

• H: rarely modified intentionally except to F

• F: very common substituent in modern drugs

• Used to tune potency, PK, & stability

What is the total number of human protein kinases?

~518

What is Imatinib?

Inhibitor of BCR-ABL, an oncogenic kinase that drives Chronic Myelogenous Leukoemia (CML) by causing uncontrolled cell signaling

What is the aromatic geometry in phenyl ring vs. pyridine ring?

• Both maintained

• Preserves 3-D shape complementarity in BCR-ABL ligand-binding pocket

What is the hydrophobicity in phenyl ring vs. pyridine ring?

• Phenyl: purely hydrophobic

• Pyridine: less hydrophobic

• Improves balance of polarity & lipophilicity in pyridine

What is the H bonding capacility in phenyl ring vs. pyridine ring?

• Phenyl: none

• Pyridine: N: as a HBA

• Enables additional H-bond formation w/ BCR-ABL

What is the polarity in phenyl ring vs. pyridine ring?

• Phenyl: nonpolar

• Pyridine: slightly more polar

• Improves H2O solubility

What is the BCR-ABL kinase selectivity in phenyl ring vs. pyridine ring?

• Phenyl: fewer specific interactions

• Pyridine: addition H-bonding interaction w/ BCR-ABL

• Improves kinase selectivity for BCR-ABL

What is the BCR-ABL inhibitory potency in phenyl ring vs. pyridine ring?

• Phenyl: moderate inhibition

• Pyridine: increased inhibitory potency (due to H-bond w/ HCR-ABL)

• Stronger & more specific binding to BCR-ABL kinase

What is the drug-like properties in phenyl ring vs. pyridine ring?

• Phenyl: lower H2O solubility & PK limitations

• Pyridine: improved H2O solubility & pharmacokinetics

• Better overall drug properties