Orally Bioavailable Macrocycles

Hurevich M, Swed A, Joubran S et al (2010) Rational conversion of noncontinuous active region in proteins into a small orally bioavailable macrocyclic drug-like molecule the HIV-1 CD4 gpl20 paradigm. Bioorg Med Chem 18 5754—5761... 

Cyclosporine A (16) is a natural product which serves as the quintessential Beyond Rule-of-5 macrocycle, able to overcome the disadvantages of high MW (1203 Daltons) and polarity (11 amide bonds) and achieve excellent absorption (Fa = 0.86). It appears able to do this by a combination of N-methylation (seven Ai-methylated amides), intramolecular hydrogen bonding (four observed in the crystal structure), a compact 3D structure incorporating p turns, and a preponderance of hydrophobic sidechains. This same feature set is seen in many of the designed orally bioavailable macrocycles in Tables 10.7 and 10.8 and perhaps most closely adopted in the design of 24. 

The authors would like to thank Huijun Wang for assistance with literature searches for orally bioavailable macrocycles. MPJ is a consultant to Schro-dinger LLC. 

A series of macrocyclic 3-aminopyrrolidinones was designed and found to act as potent famesyltransferase inhibitors." Although 6 has good oral bioavailability (F = 47%), it has a short in vivo half-life and a high clearance... 

Macrocyclization can potentially have an even greater impact on oral bioavailability by increasing the fraction absorbed (Fg). For peptides, cyclization can reduce or eliminate susceptibility to proteolytic degradation by gastric, intestinal, or brush border proteases,thereby significantly increasing the fraction of peptides available for permeation. Table 10.2 shows the stability of two cyclic peptides in brush border membrane vesicles. Cyclic peptide 6 is only 25% degraded after 90 minutes. N-methylation... 

Table 10.4 Summary of potential impact of macrocyclization on oral bioavailability.

Optimizing the Permeability and Oral Bioavailability of Macrocycles Table 10.5... 

Table 10.6 Representatives beyond Rule-of-5 macrocycles with human oral bioavailability >10%. ...

---