and strain breakage.
In 1976, Erik De Clercq (Rega Institute for Medical Research, Catholic University of Leuven, Belgium), a Belgian physician and virologist, and Antonín Holý, a Czech chemist (Czechoslowak Academy of Science, Prague) met at a symposium on synthetic nucleosides organized by the Max Planck Society and subsequently started a very successful collaboration [111]. At the time, Hóly was one of the most important chemists in Eastern Europe, De Clercq was an enthusiastic 35‐year‐old physician. In the course of this collaboration, they developed a deep and trusting relationship. Working on synthetic nucleoside analogues, they quickly discovered (S)‐9‐(2,3‐dihydroxypropyl)adenine ((S)‐DHPA, Figure 1.15), the first acyclic nucleoside analogue [112] that displayed broad antiviral activity. Stimulated by reports on antiviral activities of simple phosphonates like phosphonoacetic acid, they set out to develop bioisosteric catabolically stable nucleotide analogues. Adding a phosphonate to the primary hydroxyl group led to the active monophosphate analogue, (S)-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)‐HPMPA) (Figure 1.15) [113]. This compound displayed encouraging activity against various DNA viruses and seemed to work through a different mechanism than acyclovir, which had been described shortly before. They also discovered that the corresponding cytosine derivative ((S)‐HPMPC, Figure 1.15) possessed an antiviral spectrum comparable to that of HPMPA [114]. This compound was later approved as cidofovir. Structural simplification of (S)‐HPMPA, in particular removing the stereogenic center, led to adefovir, which was approved for treatment of hepatitis B in September 2002. Further optimization led to tenofovir, which, despite its chemical similarity, is more specific than adefovir (Figure 1.15) and does not inhibit herpesviridae. It is approved for treatment of human immunodeficiency virus (HIV), both alone and as combination therapy with emtricitabin, sold under the brand name Truvada™.
Figure 1.15 Structures of antiviral compounds developed by Hóly and De Clercq.
Tenofovir (Figure 1.15) is a prodrug that is quickly deprotected intracellularly, followed by double phosphorylation by adenosine monophosphate (AMP) kinase. The resulting triphosphate analogue cannot undergo complete dephosphorylation due to the presence of the phosphonate. Also, in contrast to other nucleotide drugs not bearing a phosphonate group (e.g. acyclovir), the activity of tenofovir does not rely on initial phosphorylation by viral kinases. It should thus possess a broad activity. It selectively inhibits the viral enzyme reverse transcriptase and displays favorable selectivity against human DNA polymerases. These compounds were originally synthesized by Hóly in the form of their free phosphonates and displayed minimal bioavailability. Only when prodrug forms were developed [115] could the compounds be quickly absorbed after oral dosing.
After the original compounds within this class were discovered in the 1980s, preclinical exploration of several derivatives was performed at Bristol‐Meyers. Upon merging with Squibb, the new company stopped projects involving these compounds, and the compound rights were returned to the inventing universities. Development of this compound class was reinitiated in 1989 by Gilead, leading to successful approval of three different new chemical entities (NCEs). In a license agreement, Gilead agreed to pay €11 million to the two universities, along with another 3% to 5% of net sales of different licensed products. Annual royalties to the Institute of Organic Chemistry and Biochemistry reached up to €90 million per year. Furthermore, in 2006 Gilead agreed to donate €1.1 million to create and sustain a Gilead Sciences Research Centre on campus. Hóly retired in 2011 and died on 16 July 16 2012, just two months after tenofovir was approved for treatment of HIV. On the very same day of Hóly's passing away, Truvada was also approved for prevention of HIV infections.
1.6.3 Darunavir
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 (KD = 4.5 × 10−12 M), which is 2 to 3 orders of magnitude higher than other HIV protease inhibitors [120].
1.6.4 Sunitinib
Inhibition of kinases, albeit omnipresent these days, is still a therapeutic principle known for less than 50 years. In 1986, Umezawa [121] reported erbstatin (Figure 1.17) as the first kinase inhibitor, targeting epidermal growth factor receptor. Because of high intracellular ATP concentrations, kinases were at that time widely believed to be undruggable. Achieving specificity seemed another impossible task considering the vast number of different kinases in the human body. However, in 1991, Joseph Schlessinger (Yale University) and Axel Ullrich (Max Planck Institute for Biochemistry in Martinsried) decided to start a company called Sugen, resulting from a collaboration of the two laboratories. The name Sugen is composed of the initials
