1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/ meta-substituted arenes

Abstract

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

Keywords: bioisosteres; medicinal chemistry; synthesis.

Fig. 1.

Introduction to bicyclo[1.1.1]pentanes as arene bioisosteres. Bridgehead functionalization of bicyclo[1.1.1]pentanes (A), need for invention: 1,2-difunctionalization of bicyclo[1.1.1]pentanes (B), and this work (C).

Fig. 2.

Preparation of diverse 1,2-difunctionalized bicyclo[1.1.1]pentane building blocks. Preparation of intermediate 1 (A), preparation of key building block 2 (B), preparation of alcohol, carboxylic acid, and amine building blocks (C), and preparation of other useful building blocks (D).

Fig. 3.

Bioisosteres synthesis (A, details can be found in SI Appendix), ADME (absorption, distribution, metabolism, and excretion) data of selected drugs and their bioisosteres: sonidegib (B), boscalid (C), meclizine (D), tolvaptan (E), phthalysulfathiazole (F), lomitapide (G), and telmisartan (H). SFLOGD, shake flask log D (good range: 1 to 3) (descriptions of methods for the SFLOGD assay can be found in SI Appendix); KS, kinetic solubility (good range: >200 μM) (39); RRCK, Ralph Russ canine kidney (good range, >10) (40); HHEP, human hepatocyte stability (good range: cline <7 μL/min) (descriptions of methods for the HHEP assay can be found in SI Appendix). NMD, nonmetabolic decline. Low risk, green; moderate risk, orange; high risk, red. Note: The data for (−)-15a and (−)-15b were not provided as they are a pair of inseparable diastereomers.

Fig. 4.

Crystal structure (A), bioassay data (B), and computational modeling (C) of axitinib bioisosteres. KDR, kinase insert domain receptor; KDR %inh, at 0.1 μM; KDR IC₅₀ unit, nM. Similar Glide scores for (+)-20 and (−)-20 (Top, subpanels A–C); the R-isostere [pink, (+)-20] amide is docked in a hydrophobic pocket (subpanel D); the S-isostere (orange, (−)-20) amide is docked near polar groups such as ASP-1046 (2.9 Å) and GLU-885 (2.6 Å) (subpanel E); 250-fold difference in potency (KDR IC₅₀) between axitinib and (−)-20; the torsion angle between the adjacent substituents on the ring: axitinib (0°, subpanel F); the S-isostere (−)-20 (67°, subpanel G); the distance between S and O: axitinib (2.9 Å, subpanel F); and (−)-20 (4.0 Å, subpanel G).