Macrocycle drug review

Here's a comprehensive and useful review of macrocycle drugs in J Med Chem by Giordanetto and Kihlberg at AstraZeneca; well worth reading to get an idea of what's out there in the clinic and on the market. 

The authors looked at about 30 clinical macrocycle candidates and 70 marketed macrocycle drugs and analyzed their principal physicochemical properties to investigate trends and differences. Some main points emerging from the discussion:

1. Most macrocycles are in oncology or infection; however, the ones that are targeted toward other areas include a significant number of de-novo synthetic or semisynthetic molecules from structure-based drug design.

2. Among marketed macrocycles, injected drugs are mostly cyclic peptides while oral drugs are mostly macrolides (in general, injectable macrocycles seem to span a broader chemical space).

3. The structural differences between oral and injectable macrocycles can often be pretty trivial (at least on inspection; eg. tacrolimus vs pimecrolimus).

4. For oral macrocycles, increasing MW seems to track with increasing lipophilicity.

5. There's a set of plots which indicates the limits of chemical space within which marketed macrocycles seem to lie. "Rogue" rule-breakers like cyclosporin which lie very far from this space are still exceptions.

The question of whether we can deliberately engineer drug molecules to act like cyclosporin on a large scale is still very much an open one. What is clear is that we are increasingly making molecules that are decidedly testing the boundaries of the rule-of-5 and pushing the envelope. The future is not guaranteed, but it's promising.