Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres.
Bicycloalkyl groups have been previously described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction into complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves aqueous solubility by at least 50-fold, and markedly decreases nonspecific binding (NSB) as measured by CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits regarding NSB or solubility, whereas substitutions with cubane-1,4-diyl showed improvements for both parameters. These results confirm the potential advantages of both BCP and cubane motifs as bioisosteric replacements for optimizing para-phenyl-substituted molecules.
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 141 Klybeckstrasse, 4057, Basel, Switzerland.
Yves P
0000-0001-5800-4811
YP
Auberson
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 141 Klybeckstrasse, 4057, Basel, Switzerland.
Cara
C
Brocklehurst
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 141 Klybeckstrasse, 4057, Basel, Switzerland.
Markus
M
Furegati
SpiroChem AG, Swiss Federal Institute of Technology (ETH) Zürich, LOC-HCI-H337, Wolfgang-Pauli Str. 10, 8093, Zürich, Switzerland.
Thomas C
TC
Fessard
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 141 Klybeckstrasse, 4057, Basel, Switzerland.
Guido
G
Koch
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 141 Klybeckstrasse, 4057, Basel, Switzerland.
Andrea
A
Decker
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 141 Klybeckstrasse, 4057, Basel, Switzerland.
Luigi
L
La Vecchia
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 141 Klybeckstrasse, 4057, Basel, Switzerland.
Emmanuelle
E
Briard
D000814:Aniline Compounds / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008567:Membranes, Artificial; D012995:Solubility
D000814:Aniline Compounds; D001643:Bridged Bicyclo Compounds; D002264:Carboxylic Acids; D008024:Ligands; D008567:Membranes, Artificial
bicycloalkyl groups; bioisosteres; imaging agents; liquid chromatography; nonspecific binding