Emphysema and elastase

A more attractive approach to the treatment of emphysema has been the design of small molecular weight inhibitors of HNE based on an understand- 

A more clinically advanced inhibitor, ICI-200880 (40), now in Phase-I trials, has been designed [82] by consideration of the transition state developed during the production of the acyl-enzyme intermediate. Compound (40) is a slow binding competitive HNE inhibitor (K = 0.5 nM) which protects in the hamster model of elastase-induced emphysema for up to 48 h following administration by aerosol [83], The trifluoromethylketone (41) is the most 

As a salutary post script to the discussion that has been presented above, a final example of innovation is presented, an example which has caused a profound change in direction in the search of anti-AIDS drugs. Until a little over a year ago, all research into inhibitors of reverse transcriptase (RT, see above) relied upon mimicry of the nucleoside substrates in the polymerase reaction. Here is an enzyme for which the reaction pathway is known only in bald outline and for which there is no structural information. Janssen s approach was masterly [84]. A library of 600 molecules, each prototypes of different chemical series and without activity in standard pharmacological assays, were screened for anti-HIV activity in vitro. It was discovered that (45) had modest but specific anti-HIV activity and lead optimisation eventually uncovered (46) and (47) as representatives of the TIBO series. It was subsequently shown that these compounds act as non-competitive inhibitors of RT, an indication that even if structural data were available, they would be useless in developing the series towards a drug candidate. As if by coincidence, several 

Other groups [85-87] have now reported structurally diverse agents (for example (48), (49) and (50)), all apparently interacting with RT in a similar manner to TIBO, possibly at an identical, or at least at an overlapping allosteric site. In almost record time, two of these drugs, (46) and (50), have proceeded into clinical trials the outcome is eagerly awaited. 

In conclusion, we are still in a position where the payoff from modern drug discovery techniques it still to be fully realised. However, it is my belief that when such techniques are combined with serendipity and the intuition of medicinal chemists, this represents as formidable a team as is possible. Given this as the current state of the art, the limiting obstacles to the design of new drug entities will continue to be pharmcokinetic affairs and it is in this area that a predictive black box would be most beneficial. 

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