Structure-based characterization and optimization of novel hydrophobic binding interactions in a series of pyrrolidine influenza neuraminidase inhibitors.
The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.
Maring
Clarence J
CJ
Department of Infectious Disease Research and Advanced Technology, Global Pharmaceutical R & D, Abbott Laboratories, Abbott Park, Illinois 60064, USA. clarence.maring@abbott.com
Stoll
Vincent S
VS
Zhao
Chen
C
Sun
Minghua
M
Krueger
Allan C
AC
Stewart
Kent D
KD
Madigan
Darold L
DL
Kati
Warren M
WM
Xu
Yibo
Y
Carrick
Robert J
RJ
Montgomery
Debra A
DA
Kempf-Grote
Anita
A
Marsh
Kennan C
KC
Molla
Akhteruzzaman
A
Steffy
Kevin R
KR
Sham
Hing L
HL
Laver
W Graeme
WG
Gu
Yu-gui
YG
Kempf
Dale J
DJ
Kohlbrenner
William E
WE
D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D009980:Influenza A virus / Q000201:enzymology*; D009981:Influenza B virus / Q000201:enzymology*; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011759:Pyrrolidines; D009439:Neuraminidase