The fragment of benzene is the most popular ring in bioactive compounds. In fact, more than 500 drugs and agrochemicals are benzene-containing molecules. In 2012, chemists at Pfizer replaced the substituted phenyl fragment in a ɣ-secretase inhibitor Avagacestat with the bicyclo[1.1.1]pentyl skeleton. The obtained analogue showed higher activity, solubility and metabolic stability. Since then, bicyclo[1.1.1]pentanes, bicyclo[2.2.2]octanes and cubanes are used in medicinal chemistry as saturated bioisosteres for para-substituted benzenes. Therefore, here we have designed and synthesized saturated mimetics for ortho-substituted benzenes.

Design and offered structures you can find at MedChem Highlights section of Enamine’s website or in the white paper attachment.