Design and syntheses of 1,6-naphthalene derivatives as selective HCMV protease inhibitors.
Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d-i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.
Gopalsamy
Ariamala
A
Chemical and Screening Sciences and Infectious Diseases,Wyeth Research, Pearl River, NY 10965, USA. gopalsa@wyeth.com
Lim
Kitae
K
Ellingboe
John W
JW
Mitsner
Boris
B
Nikitenko
Antonia
A
Upeslacis
Janis
J
Mansour
Tarek S
TS
Olson
Matthew W
MW
Bebernitz
Geraldine A
GA
Grinberg
Diane
D
Feld
Boris
B
Moy
Franklin J
FJ
O'Connell
John
J
D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D003587:Cytomegalovirus / Q000737:chemistry*; D016208:Databases, Factual; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry
C485102:C,C,C-trifluoro-N-(5-(2-pyridin-2-ylvinyl)naphthalen-2-yl)methanesulfonamide; D009281:Naphthalenes; D011480:Protease Inhibitors; D013449:Sulfonamides; D015081:2-Naphthylamine; D012697:Serine Endopeptidases; C071910:assemblin