Emerging therapeutic opportunities for integrin inhibitors.

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbß3, α4ß7/α4ß1 and αLß2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvß3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvß6 and αvß1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.

Lead optimization in 12 months? True confessions of a chemistry team.

In 1998 GlaxoWellcome embarked upon a new enzyme-inhibitor programme. This programme featured an aggressive timeframe of seven years, from the start of medicinal chemistry through to drug launch. This period, dominated as it was by the constraints of the clinical programme, translated into a lead-optimization phase of no more than 12 months. In this article, we describe our attempts to meet this target, examining not only what we did and what worked, but also what didn't work and, most importantly, what we learnt as a result. At a time of considerable upheaval and challenge to the traditional model of drug discovery, we hope our experiences might stimulate interest, empathy and further discussion.