Oxetanes in drug discovery: structural and synthetic insights.
An oxetane can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups. The magnitude of these changes depends on the structural context. Thus, by substitution of a gem-dimethyl group with an oxetane, aqueous solubility may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degradation in most cases. The incorporation of an oxetane into an aliphatic chain can cause conformational changes favoring synclinal rather than antiplanar arrangements of the chain. Additionally spirocyclic oxetanes (e.g., 2-oxa-6-aza-spiro[3.3]heptane) bear remarkable analogies to commonly used fragments in drug discovery, such as morpholine, and are even able to supplant the latter in its solubilizing ability. A rich chemistry of oxetan-3-one and derived Michael acceptors provide venues for the preparation of a broad variety of novel oxetanes not previously documented, thus providing the foundation for their broad use in chemistry and drug discovery.
Wuitschik
Georg
G
Laboratorium fur Organische Chemie, ETH Honggerberg, HCI H335, 8093 Zurich, Switzerland.
Carreira
Erick M
EM
Wagner
Björn
B
Fischer
Holger
H
Parrilla
Isabelle
I
Schuler
Franz
F
Rogers-Evans
Mark
M
Müller
Klaus
K
D000818:Animals; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004355:Drug Stability; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D012995:Solubility; D013329:Structure-Activity Relationship
D004988:Ethers, Cyclic; C005287:oxetane