2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring.

The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties - 2-oxabicyclo[2.2.2]octane. The design of the structure is based on the analysis of the advantages and disadvantages of the previously used bioisosteres: bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and cubane. The key synthesis step is the iodocyclization of cyclohexane-containing alkenyl alcohols with molecular iodine in acetonitrile. 2-Oxabicyclo[2.2.2]octane core is incorporated into the structure of Imatinib and Vorinostat (SAHA) drugs instead of the phenyl ring. In Imatinib, such replacement leads to improvement of physicochemical properties: increased water solubility, enhanced metabolic stability, and reduced lipophilicity. In Vorinostat, such replacement results in a new bioactive analog of the drug. This study enhances the repertoire of available saturated bioisosteres of (hetero)aromatic rings for the use in drug discovery projects.

1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine.

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2 S-NCO, to give spirocyclic ß-lactams. Reduction of the ß-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent-free analogue with high activity.

Mono- and Difluorinated Saturated Heterocyclic Amines for Drug Discovery: Systematic Study of Their Physicochemical Properties.

A comprehensive study of physicochemical properties (pKa , LogP, and intrinsic microsomal clearance) within the series of mono- and difluorinated azetidine, pyrrolidine, and piperidine derivatives was performed. While the number of fluorine atoms and their distance to the protonation center were the major factors defining the compound's basicity, both pKa and LogP values were affected considerably by the conformational preferences of the corresponding derivatives. For example, features of "Janus face" (facially polarized) cyclic compounds (i. e., unusually high hydrophilicity) were identified for cis-3,5-difluoropiperidine, preferring a diaxial conformation. Intrinsic microsomal clearance measurements demonstrated high metabolic stability of the compounds studied (with a single exception of the 3,3-difluoroazetidine derivative). According to pKa - LogP plots, the title compounds provide a valuable extension of the fluorine-containing (e. g., fluoroalkyl-substituted) saturated heterocyclic amine series as building blocks for rational optimization studies in early drug discovery.

General Synthesis of 3-Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres.

A general approach to 3-azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability of this transformation were studied. The core was incorporated into the structure of the antihistamine drug Rupatidine instead of the pyridine ring, which led to a dramatic improvement in physicochemical properties.