title: Structure-based characterization and optimization of novel hydrophobic binding interactions in a series of pyrrolidine influenza neuraminidase inhibitors.
abstract: 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.
authors.affiliation: Department of Infectious Disease Research and Advanced Technology, Global Pharmaceutical R & D, Abbott Laboratories, Abbott Park, Illinois 60064, USA. clarence.maring@abbott.com
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Maring
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Minghua
authors.initials: M
authors.lastname: Sun
authors.forename: Allan C
authors.initials: AC
authors.lastname: Krueger
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Darold L
authors.initials: DL
authors.lastname: Madigan
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.forename: Yibo
authors.initials: Y
authors.lastname: Xu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Carrick
authors.forename: Debra A
authors.initials: DA
authors.lastname: Montgomery
authors.forename: Anita
authors.initials: A
authors.lastname: Kempf-Grote
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Steffy
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: W Graeme
authors.initials: WG
authors.lastname: Laver
authors.forename: Yu-gui
authors.initials: YG
authors.lastname: Gu
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: William E
authors.initials: WE
authors.lastname: Kohlbrenner
mesh_terms: 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
chemical_list: D011759:Pyrrolidines; D009439:Neuraminidase