Indinavir SAR table

It is perhaps not surprising that we have chosen three anti-HIV drug discovery projects. The failure to find a vaccine for HIV, in the second half of the eighties, launched a concerted push to develop small molecule drugs. This was building on the success of the nucleoside reverse transcriptase inhibitors (NRTI) compounds such as AZT. This effort coincided with improved Structure Based Drug Design (SBDD) via co-crystals and 3D modelling, and higher through-put in-vitro assays. The protease of HIV had been discovered and early compounds were shown to reduce virus load in-vitro. Using the transition state isostere concept hydroxyethylene dipeptide isostere inhibitors were designed and known. The story of the discovery of Indinavir starts with their own in-house inhibitors, and an early compound from Roche. These compounds had poor aqueous solubility and no bio-availability, but with 3D modelling the researches saw the opportunity of taking the basic nitrogen groups from the Roche compound into their series and this led to Indinavir.

Indinavir; L-735,524: The Design of a Potent and Orally Bioavailable HIV Protease Inhibitor.

J. Med. Chem. 1994, 37, 21, 3443–3451

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