1,1'-Biphenyl

The 1,1'-Biphenyl scaffold is well established as a privileged structure in medicinal chemistry, recognised for its capacity to engage diverse protein targets through hydrophobic contacts and π-stacking interactions. The two phenyl rings adopt a near-planar geometry in solution, providing a defined vector for the presentation of pharmacophoric groups, while ortho-substitution can impose restricted rotation about the biaryl bond, giving rise to stable atropisomers with distinct binding profiles. Biphenyl scaffolds have shown a wide range of biological activities including anti-inflammatory, antihypertensive, treatment of CNS disorders, anti-cancer, and anti-HIV applications, and the importance of biphenyl atropisomers is well recognised.

In the context of rational drug design, the biphenyl linker serves as a rigid spacer that positions terminal pharmacophores at a defined distance and angle, reducing the entropic cost of binding and enabling simultaneous occupation of spatially separated sub-pockets within a target binding site. The biphenyl linker provides an optimal spatial distance between pharmacophores, and this structural rigidification is essential for minimising the entropic penalty upon binding. SAR investigations across multiple programmes have demonstrated that substitution topology on the biphenyl core is a key determinant of both potency and selectivity, with the 4,4'- and 3,4'-substitution patterns frequently conferring distinct activity profiles depending on target geometry.

The antihypertensive class of angiotensin II receptor blockers (ARBs) provides the clearest clinical validation of the biphenyl scaffold in small-molecule drug discovery. Losartan potassium (Cozaar), the first angiotensin II receptor blocker to enter the market, contains a biphenyl group with a tetrazole bioisostere and was approved by the FDA in 1995, marking a significant advance in RAAS inhibition by delivering effective blood pressure control without the cough or angioedema associated with ACE inhibitors. Sonidegib (Odomzo, Novartis) is an FDA-approved oral Smoothened antagonist built around a [1,1'-biphenyl]-3-carboxamide scaffold confirmed in the FDA label chemical name, approved in July 2015 for the treatment of adults with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or for those ineligible for such treatment, where the biphenyl core positions a 2-methyl-3-carboxamide group on the proximal ring and a 4'-trifluoromethoxy substituent on the distal ring, with the rigid planar biphenyl framework projecting the carboxamide into the Smoothened binding site to achieve potent inhibition of Hedgehog pathway signalling at nanomolar concentrations. Both compounds illustrate how the biphenyl scaffold can be decorated with acidic heterocycles and aliphatic side chains to achieve selective receptor engagement across a well-validated cardiovascular target class.

Our range of 1,1'-Biphenyls 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 1,1'-Biphenyls in our catalogue. The full range can be found using the substructure feature of our Search tools.