Non-steroidal antiandrogens. Design of novel compounds based on an infrared study of the dominant conformation and hydrogen-bonding properties of a series of anilide antiandrogens.
Antiandrogenic activity is observed in anilides containing a tertiary hydroxyl group, and these compounds are used to define a pharmacophore in terms of their physicochemical properties. Infrared spectroscopy shows that these anilides exist in a single conformation, which exerts a powerful influence on the hydrogen-bond donor ability of the hydroxyl group in a model system. Arguments are presented which suggest that hydrogen-bonding ability is an important contributor to biological activity. Compounds were synthesized that reproduced these properties in series not containing an amide bond. Such compounds were found to exhibit good antiandrogen activity. We suggest that quantitative information on hydrogen bonding might also be useful in other systems.
Morris
J J
JJ
ICI Pharmaceuticals, Mereside, Macclesfield, Cheshire, United Kingdom.
Hughes
L R
LR
Glen
A T
AT
Taylor
P J
PJ
D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000726:Androgen Antagonists; D000813:Anilides; D007202:Indicators and Reagents; D011944:Receptors, Androgen