Cyclopropane

The cyclopropane ring is one of the most widely deployed small-ring carbocycles in modern drug discovery, appearing across a broad spectrum of therapeutic areas as both a core scaffold and a peripheral substituent. Important features of the cyclopropane ring include the coplanarity of its three carbon atoms, relatively shorter C-C bonds, enhanced π-character of C-C bonds, and C-H bonds that are shorter and stronger than those in alkanes. These properties combine to produce an electronically distinctive fragment that behaves as a partial alkene, influencing the pKa of adjacent functional groups, restricting conformation, and modulating lipophilicity without substantially increasing molecular weight. The cyclopropyl ring addresses multiple roadblocks that arise during drug discovery, including enhancing potency, reducing off-target effects, increasing metabolic stability, improving brain permeability, decreasing plasma clearance, contributing to an entropically more favourable receptor binding, and restricting the conformation of peptidomimetics to prevent proteolytic hydrolysis.

The cyclopropyl group frequently serves as a bioisostere for alkenes, gem-dimethyl groups, or even monosubstituted arenes, where it can improve the balance of properties in a lead series without requiring major scaffold changes. Between 2012 and 2018, the FDA approved 18 new drugs that incorporate the cyclopropyl structural motif, reflecting both the breadth of its utility and the maturity of synthetic methods available to introduce it reliably into complex molecules.

Examples of cyclopropyl in the clinic include Deucravacitinib (Sotyktu, Bristol Myers Squibb), a first-in-class, oral, selective, allosteric TYK2 inhibitor approved by the FDA in September 2022 for moderate-to-severe plaque psoriasis, which contains a cyclopropanecarboxamide group that contributes to the compound's binding to the pseudokinase regulatory domain of TYK2. Ticagrelor (Brilinta, AstraZeneca), approved by the FDA in 2011 as the first reversibly-binding oral P2Y12 receptor antagonist, is a cyclopentyltriazolopyrimidine that contains a difluorophenylcyclopropylamine substituent, with the cyclopropyl unit playing a direct role in shaping the geometry of the molecule's interaction with the receptor.

Our range of cyclopropyls features novel substitutions and the incorporation of synthetically tractable functional groups such as boronic acids and esters, amines, carboxylic acids, ketones, hydroxyls and halogens to enable expedient synthetic strategies.

Please examine a selection of cyclopropyls in our catalogue. The full range can be found using the substructure feature of our Search tools.