title: Syntheses and neuraminidase inhibitory activity of multisubstituted cyclopentane amide derivatives.
abstract: In further studies aimed toward identifying effective and safe inhibitors of influenza neuraminidases, we synthesized a series of multisubstituted cyclopentane amide derivatives. Amides prepared were 14 examples of N-substituted alkyl or aralkyl types from primary amines, 13 examples of the N,N-disubstituted alkyl, aralkyl, or substituted-alkyl type from secondary amines, and 12 examples from cycloaliphatic or substituted cycloaliphatic secondary amines. These compounds bearing two chiral centers, at position-1 in the ring and position-1' in the side chain attached at position 3, were tested for their ability to inhibit A and B forms of influenza neuraminidase. The 1-ethylpropylamide, diethylamide, dipropylamide, and 4-morpholinylamide showed very good inhibitory activity (IC(50) = 0.015-0.080 microM) vs the neuraminidase A form, but modest activity (IC(50) = 3.0-9.2 microM) vs the neuraminidase B form. Since the parent amides bear two chiral centers (C-1 and C-1'), three of the better inhibitors were tested at higher levels of diastereomeric purity. The diastereomers corresponding to the active forms of the 1-(ethyl)propylamide, the diethylamide, and the dipropylamide (all of the same configuration at the C-1' chiral center), and the diastereomer of the diethylamide representing the active form at both C-1' and C-1 were isolated or synthesized from precursors that were isolated as diastereomers. These diastereomers showed some improvement in neuraminidase inhibition over the parent diastereomeric mixtures. 1-Carboxy-1-hydroxy derivatives of the best active compounds, the diethylamide and the dipropylamide, were also prepared. These compounds were not as active as the compounds without the 1-hydroxy group. In an in vivo study, the C-1' active isomer of the diethylamide from the 1-carboxy series was tested in influenza-infected mice by oral and intranasal administration and found to be very effective only intranasally in preventing weight loss at doses as low as 0.1 (mg/kg)/day.
authors.affiliation: BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA. pchand@biocryst.com
authors.forename: Pooran
authors.initials: P
authors.lastname: Chand
authors.forename: Y Sudhakar
authors.initials: YS
authors.lastname: Babu
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.forename: Scott
authors.initials: S
authors.lastname: Rowland
authors.forename: Ali
authors.initials: A
authors.lastname: Dehghani
authors.forename: Pravin L
authors.initials: PL
authors.lastname: Kotian
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hutchison
authors.forename: Shoukath
authors.initials: S
authors.lastname: Ali
authors.forename: Wayne
authors.initials: W
authors.lastname: Brouillette
authors.forename: Yahya
authors.initials: Y
authors.lastname: El-Kattan
authors.forename: Tsu-Hsing
authors.initials: TH
authors.lastname: Lin
mesh_terms: D000281:Administration, Intranasal; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009980:Influenza A virus / Q000201:enzymology; D051379:Mice; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000998:Antiviral Agents; D003517:Cyclopentanes; D009439:Neuraminidase