Discovery of a potent, selective and orally bioavailable 3,9-diazaspiro[5.5]undeca-2-one CCR5 antagonist.
Replacement of the cyclic carbamate in our previously disclosed 1-oxa-3,9-diazaspiro[5.5]undecan-2-one template led to the discovery of two novel series of 3,9-diazaspiro[5.5]undecane and undeca-2-one CCR5 antagonists. The synthesis, SAR, and antiviral activities of these two series are described. One compound (32) was found to have attractive combination of antiviral potency, selectivity, and pharmacokinetic profile. The asymmetric synthesis of 32 was also accomplished and both enantiomers were equally potent.
Yang
Hanbiao
H
Roche Palo Alto LLC, Palo Alto, CA 94304, USA. hanbiaoyang@gmail.com
Lin
Xiao-Fa
XF
Padilla
Fernando
F
Gabriel
Stephen D
SD
Heilek
Gabrielle
G
Ji
Changhua
C
Sankuratri
Surya
S
deRosier
André
A
Berry
Pamela
P
Rotstein
David M
DM
D000284:Administration, Oral; D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D055808:Drug Discovery; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000473:Alkanes; D000998:Antiviral Agents; D065100:CCR5 Receptor Antagonists; D013141:Spiro Compounds; C022884:undecane