Review: Bioisosteres in Drug Design

An excellent J.Med.Chem. perspective titled ‘Synopsis of Some Recent Tactical Applications of Bioisosteres in Drug Design‘ has just published (The article is based on a short course presented at an ACS Prospectives conference in 2009).  The author gives a brief introduction to the concept of biosisosterism (classical and non-classical) but concentrates on pulling together numerous recent examples which together illustrate the use of bioisosteres to address a diverse range of issues that are commonly encountered in the process of drug discovery.  Whilst he expressly states the intention to avoid compiling a comprehensive catalogue of bioisosteres the paper does, nonetheless, cover a wide range of isosteres and  it  includes a lot of data and primary references that will serve as key resource material for medicinal chemists.  A really nice paper and highly recommended reading material.

  • Isosteres of Hydrogen:
    • Deuterium as an isostere of hydrogen.
    • Deuterium substitution to modulate metabolism.
    • Deuterium substitution to modulate metabolism and toxicity.
    • Deuterium to slow epimerization.
    • Fluorine as an isostere of hydrogen.
    • Fluorine for hydrogen exchange to modulate metabolism.
    • Deploying fluorine to modulate basicity in KSP inhibitors.
    • Substitution of hydrogen by fluorine as a strategy for influencing conformation.
    • Fluorine/hydrogen exchange to influence membrane permeability.
  • Isosteres of Carbon and Alkyl Moieties:
    • CH2, O, and S isosterism.
    • CH2/O isosterism in PGI2 mimetics.
    • CH2/O isosterism in non-prostanoid PGI2 mimetics.
    • Silicon as an isostere of carbon.
    • Silicon in p38α MAP kinase inhibitors.
    • Silicon as a carbon isostere in biogenic amine reuptake inhibitors.
    • Silicon as a carbon isostere in haloperidol.
    • Silicon/carbon isosterism in retinoids.
    • Silicon/carbon exchange in protease inhibitors.
    • Silanediols as HIV-1 protease inhibitors.
    • Silanediols in ACE inhibitors.
    • Silicon in thermolysin inhibitors.
    • Cyclopropyl rings as alkyl isosteres.
    • Cyclopropyl in T-Type calcium channel antagonists.
    • Cyclopropyl in CRF-1 antagonists.
    • Oxetanes as mimetics of alkyl moieties.
    • CF3 as a substitute for methyl in a tert-butyl moiety.
    • CF2 as an isostere of C(CH3)2.
  • N Substitution for CH in Benzene Rings:
    • N for CH in phenyl rings in CRF-1 antagonists.
    • N for CH in phenyl rings in calcium sensing receptor antagonists.
    • N for C substitution in dihydropyridine derivatives.
  • Biphenyl and Phenyl Mimetics:
    • Biphenyl mimetics in factor Xa inhibitors.
    • Phenyl mimetics in glutamate antagonists.
    • Phenyl mimetics in oxytocin antagonists.
  • Phenol, Alcohol, and Thiol Isosteres:
    • Phenol and catechol isosteres.
    • Phenol isosteres in dopamine D1/D5 antagonists.
    • Alcohol and thiol mimetics:
      • Sulfoximine moiety as an alcohol isostere.
      • RCHF2 as an isostere of ROH.
      • RCHF2 as a thiol mimetic in HCV NS3 protease inhibitors.
      • Application of RCHF2 as an alcohol isostere in lysophosphatidic acid.
  • Hydroxamic Acid Isosteres:
    • Application of RCHF2 to hydroxamic acid isosteres.
    • Hydroxamic acids in carbonic anhydrase II inhibitors.
    • Hydroxamic acid mimetics in TNFα-converting enzyme (TACE) inhibitors.
  • Carboxylic Acid Isosteres:
    • Carboxylic acid isosteres in angiotensin II receptor antagonists.
    • Acylsulfonamide in HCV NS3 protease inhibitors.
    • Acylsulfonamide in EP3 antagonists.
    • Acylsulfonamides in Bcl-2 inhibitors.
    • 2,6-Difluorophenol as a CO2H mimetic.
    • Squaric acid derivatives as CO2H mimetics.
    • Aminosquarate derivatives as amino acid mimetics.
    • Heterocycles as amino acid mimetics.
  • Isosteres of Heterocycles:
    • Avoiding quinonediimine formation in bradykinin B1 antagonists.
    • Isosterism between heterocycles in drug design.
    • Heterocycles as hydrogen bond acceptors.
    • H-bonding capacity of common functional groups.
    • Heterocycles and H-bonds: Filling the gaps.
    • H-bonding and Brønsted basicity differences.
    • Pyridazine H-bonding in p38α MAP kinase inhibitors.
    • Heterocycle substituents and H-bonding.
    • Heterocycle isosteres in p38α MAP kinase inhibitors.
    • Heteroatoms as H-bond acceptors.
    • Oxygen atoms and H-bonding.
    • Isosterism between heterocycles in non-prostanoid PGI2 mimetics.
    • Isosterism between heterocycles in estradiol 17β-dehydrogenase inhibitors.
    • Role of pyrimidine nitrogen atoms in cathepsin S inhibitors.
    • Heterocycles and metal coordination.
    • Heterocycles and C-H bonding.
    • Heterocycle C-H bond donors in GSK3 inhibitors.
    • Evolution of GSK3 inhibitors.
    • Janus kinase 2 (JAK2) inhibitors.
    • Electron demand of heterocycles and applications.
    • Heterocycles and activation of a C=O in serine protease inhibitors.
  • Isosteres of the Nitro Group:
    • Nitro isosteres in α1α adrenoreceptor antagonists.
  • Isosteres of Carbonyl Moieties:
    • Ketone isosteres.
    • Oxetane as a C=O isostere.
    • Fluorine as a C=O isostere in factor VIIa and thrombin inhibitors.
    • Fluorine as a C=O isostere in FKBP12 mimetics.
    • Amide and ester isosteres.
    • Trifluoroethylamines as amide isosteres.
    • Trifluoroethylamines as amide isosteres in cathepsin K inhibitors.
    • Trifluoroethylamine as an amide replacement in the HCV NS3 inhibitor Telaprevir.
    • Amide isosteres in adenosine 2B antagonists.
  • Ether/sulfone and glyoxamide/sulfone isosterism:
    • Ether/sulfone isosterism in HIV-1 protease inhibitors.
    • Sulfone/glyoxamide isosterism in HIV attachment inhibitors.
  • Urea isosteres:
    • Urea isosteres in histamine antagonists.
    • Urea-type isosteres in KATP openers.
    • Urea isosteres in CXCR2 antagonists.
    • Additional squaric acid urea isosteres.
    • Urea/thiourea isosteres in factor Xa inhibitors.
  • Guanidine and Amidine Isosteres:
    • Arginine isosteres in factor Xa inhibitors.
  • Phosphate and Pyrophosphate Isosteres:
    • Phosphate and pyrophosphate mimetics.
    • Phosphate isosteres in PTP-1B.
    • Squarates as phosphate isosteres.
    • HIV-1 integrase inhibitors and phosphate isosterism.
    • Phosphate isosteres in HIV-1 RNase H and HCV NS5B inhibitors.
    • Pyrophosphate isosteres in Ras inhibitors.
    • Phosphate isosteres in HIV-1 reverse transcriptase substrates.
    • Phosphate isosterism in balanol.
    • Phosphate shape mimetics.
  • Isosteres of Ligand-Water Complexes:
    • Displacing water from the binding site of HIV-1 protease.
    • Displacing water in poly(ADP-ribose) polymerase-1 (PARP) inhibitors.
    • Displacing water in scytalone dehydratase.
    • Displacing water in p38α MAP kinase inhibitors.
    • Displacing water in epidermal growth factor receptor kinase inhibitors.
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