¹ Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres

ChemMedChem 2017, 12, 590 - 598

The replacement of phenyl rings by cage like alkyl motifs in drug candidates and drug-like compounds representing 11 distinct chemotypes was evaluated:

The effect of 2D -> 3D switch on solubility is particularly significative with cubane (~ 10 fold) and BCP (20 to 50 fold) motifs:

² Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

ChemMedChem 2016, 11, 31 – 37

Imatinib has:

• A high density of aromatic rings (Fsp³ = 0.24)
• A high calculated lipophilicity (clog P= 4.53)

This combination of properties is reflected in its very low aqueous solubility (0.01mg/mL), making the free base nearly insoluble in neutral aqueous media.

By replacing the 1,4-disubstituted phenyl ring of Imitanib with sp³ three-dimensional structural motifs, Nicolaou and coworkers clearly shifted the molecules into a more polar space.

³ Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres

ChemMedChem 2017, 12, 590 – 598

Para substituted phenyl rings can be isosterically replaced by rigid nonconjugated hydrocarbons linkers. The distance between bridge heads can be modulated and tuned depending on the choice of the sp³ system. Interestingly, the distance between connecting atoms in the bicyclooctane and cubane systems are very similar to the one in the para-phenyl ring, while it is 35% smaller in the bicyclopentane system.

To optimize binding, length and angle fine-tuning is also possible with [3.2.2]nonane, [2.1.1]hexane and [2.2.1]heptane systems.

^4a Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism

Chem. Res. Toxicol. 2017, 20, 30(2), 642-656

In 2007, Australia's Therapeutic Goods Administration cancelled the registration of Lumiracoxib, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), due to concerns that it may cause liver failure.

Indeed, the quinone-imine leads to the formation of the hapten complex with off-target proteins that triggers toxic immune responses and then hepatotoxicity.

Replacement of the phenyl ring by sp³ systems could prevent the formation of the hapten complex.

^4b Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4

Drug Metabolism and Disposition 2005, 33 (2), 243-253

Nefazodone is an antidepressant with a severe hepatotoxicity which has led to its withdrawal from the market. It first undergoes aromatic hydroxylation to form hydroxy-nefadozone, which is then oxidized to form the reactive nefadozone quinone, thereby causing hepatotoxicity in some patients.

Replacing the phenyl ring by an sp³ ring would be a good strategy to circumvet metabolic hydroxylation.

^5a Metabolism-dependent neutrophil cytotoxicity of amodiaquine: a comparison with pyronaridine and related antimalarial drugs

Chem. Res. Toxicol. 1998, 11, 1586-1595

Amodiaquine is a 4-aminoquinoline derivative, which was widely used in the past for both prophylaxis and treatment of malaria. It was withdrawn from use because of fatal side effects, notably agranulocytosis and hepatitis, which occurred mainly in non-immune adults taking the drug for prophylaxis.

Toxicity problems have been attributed to  the formation of a quinone-imine metabolite, which undergoes nucleophilic attack (preferentially with nucleophilic thiol group).

Replacing the 4-aminophenol ring by a constrained sp³ amino alcohol would be a good alternative to alleviate metabolism related issues.

^5b Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

Drug Metab Dispo. 2012, 40(1), 139-150

Lapatinib is an important orally active dual tyrosine kinase inhibitor efficacious in combination therapy for patients with metastatic breast cancer. However, clinically significant liver injury, which may be associated with lapatinib metabolic activation, has been reported. Several of the lapatinib metabolites can undoubtedly be linked to fluorobenzyl oxidative cleavage and formation of reactive species such as quinone imines.

Replacement of phenyl rings by cage like alkyl motifs could alleviate metabolism issues:

⁶ Preparation of bicycloalkanecarboxamides and related compounds as modulators of the integrated stress pathway

WO2019090076

Para dianiline derivatives are considered as ones of the highest structural alerts:

To circumvent such issue, Calico Life Sciences describes the preparation of eIF2B modulators (e.g., eIF2B activators) of Formula (I) where di-amino cage like alkyl motifs are the core of the molecules.

Many derivatives are active in a cellular assay with an ATF4-_Luc EC₅₀ below 50 nM, as the following BCP and BCO derivatives:

⁷ Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA₂ Inhibitor

Angew. Chem. Int. Ed. 2017, 56, 5684 - 5718

ɣ-Secretase inhibitors are of interest for the treatment of Alzheimer’s disease since the enzyme plays a key role in the production of ß-amyloid peptides (Aß).

The replacement of the fluorophenyl ring of the ɣ-secretase inhibitor BMS708-163 (IC₅₀ (Aß42)= 0.225 nm) developed by Pfizer with a bicyclo[1.1.1]pentane moiety led to an even more potent inhibitor (IC₅₀ (Aß42)=0.178 nm).

Very interestingly, this analogue also showed improved aqueous solubility and passive permeability, as well as improved oral absorption in a mouse model of ɣ-secretase inhibition.

⁸ Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

J. Am. Chem. Soc. 2016, 138, 1698-1708.

The impressive biological properties of tubulysins coupled with their natural scarcity stimulated intense research activities directed towards their chemical synthesis, structural modification, and biological evaluation. They are of particular interest as payloads for antibody−drug conjugates (ADCs) and probody−drug conjugates (PDCs) where extremely high potencies are desirable.

The SAR exploration of the east part of the molecule led to the identification of a TB1 BCP-derivative with excellent inhibitory activity against various human cancer cell lines, for example, GI₅₀=64 pm (growth inhibition) against a leukemia cell line.

⁸ Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

J. Am. Chem. Soc. 2016, 138, 1698-1708.

The impressive biological properties of tubulysins coupled with their natural scarcity stimulated intense research activities directed towards their chemical synthesis, structural modification, and biological evaluation. They are of particular interest as payloads for antibody−drug conjugates (ADCs) and probody−drug conjugates (PDCs) where extremely high potencies are desirable.

The SAR exploration of the east part of the molecule led to the identification of a TB1 BCP-derivative with excellent inhibitory activity against various human cancer cell lines, for example, GI₅₀=64 pm (growth inhibition) against a leukemia cell line.