Читать книгу Successful Drug Discovery, Volume 5 - Группа авторов - Страница 32

Arun Ghosh worked for several years with Merck & Co, where he acquired in‐depth experience with the development of protease inhibitors. In 1994 he started his academic career in an independent laboratory at the University of Illinois‐Chicago before moving to Purdue University in 2005. At the time that Ghosh entered academia, the HIV pandemic represented a global healthcare burden with no therapy available. The development of protease inhibitors was an active research area with great promise, but their use was associated with rapid development of resistance. Ghosh decided to tackle the problem of resistance development, pursuing a strictly structure‐based approach starting from the X‐ray structure of saquinavir bound to HIV protease. Saquinavir (Figure 1.16), developed by Roche, was the first inhibitor of HIV protease to obtain FDA approval in 1995. Its bioavailability is low and resistance occurs quickly with G48V being the key signature residue mutation of HIV‐1 protease [116].

The approach pursued by the Ghosh group was to maximize interactions with the active site while simultaneously improving the overall compound properties, specifically the bioavailability. They assumed that the presence of multiple amide bonds could hamper compound absorption and tried to replace these by ether or sulfone groups. Furthermore, a thorough structural examination of multiple HIV mutants suggested that the protein backbone within the active site should superimpose very well for mutant proteases and only show minimal distortions, making this an optimal interaction point to maintain activity against these mutants [117].

Thorough compound optimization [118] led to the development of TMC‐126 (Figure 1.16), which displayed impressive activity against the wild‐type enzyme as well as against a wide range of mutants. Development of viral resistance against TMC‐126 was delayed, and the resulting mutants were still sensitive to the vast majority of other protease inhibitors, rendering the drug optimal for combination therapy.

Figure 1.16 HIV protease inhibitors.

Preclinical PK studies in rodents and dogs indicated low plasma levels of TMC‐126. Further SAR studies led to the discovery of TMC‐114, which later was termed darunavir in honor of its discoverer, Arun Ghosh [119]. In 1999, under the trade name Prezista™, darunavir was licensed to Tibotec Therapeutics, which was eventually acquired by Janssen Pharma. Darunavir was FDA approved in 2006. It is part of several combination products and is also listed on the World Health Organization's list of essential medicines. It displays exceptionally high binding potency (K_D = 4.5 × 10⁻¹² M), which is 2 to 3 orders of magnitude higher than other HIV protease inhibitors [120].