N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation.
A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.
Discovery Chemistry, Analytical Research & Development, Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA.
Alexandra A
AA
Nirschl
Yan
Y
Zou
Stanley R
SR
Krystek
James C
JC
Sutton
Ligaya M
LM
Simpkins
John A
JA
Lupisella
Joyce E
JE
Kuhns
Ramakrishna
R
Seethala
Rajasree
R
Golla
Paul G
PG
Sleph
Blake C
BC
Beehler
Gary J
GJ
Grover
Donald
D
Egan
Aberra
A
Fura
Viral P
VP
Vyas
Yi-Xin
YX
Li
John S
JS
Sack
Kevin F
KF
Kish
Yongmi
Y
An
James A
JA
Bryson
Jack Z
JZ
Gougoutas
John
J
DiMarco
Robert
R
Zahler
Jacek
J
Ostrowski
Lawrence G
LG
Hamann
D000728:Androgens; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism*; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
D000728:Androgens; D010080:Oxazoles; C064210:oxazolidine