Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
Sweeney
Zachary K
ZK
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. zachary.sweeney@roche.com
Dunn
James P
JP
Li
Yu
Y
Heilek
Gabrielle
G
Dunten
Pete
P
Elworthy
Todd R
TR
Han
Xiaochun
X
Harris
Seth F
SF
Hirschfeld
Donald R
DR
Hogg
J Heather
JH
Huber
Walter
W
Kaiser
Ann C
AC
Kertesz
Denis J
DJ
Kim
Woongki
W
Mirzadegan
Taraneh
T
Roepel
Michael G
MG
Saito
Y David
YD
Silva
Tania M P C
TM
Swallow
Steven
S
Tracy
Jahari L
JL
Villasenor
Armando
A
Vora
Harit
H
Zhou
Amy S
AS
Klumpp
Klaus
K
D000818:Animals; D004285:Dogs; D024882:Drug Resistance, Viral / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D011724:Pyridazines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase