Syntheses and neuraminidase inhibitory activity of multisubstituted cyclopentane amide derivatives.
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.
Chand
Pooran
P
BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA. pchand@biocryst.com
Babu
Y Sudhakar
YS
Bantia
Shanta
S
Rowland
Scott
S
Dehghani
Ali
A
Kotian
Pravin L
PL
Hutchison
Tracy L
TL
Ali
Shoukath
S
Brouillette
Wayne
W
El-Kattan
Yahya
Y
Lin
Tsu-Hsing
TH
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
D000577:Amides; D000998:Antiviral Agents; D003517:Cyclopentanes; D009439:Neuraminidase