Design and synthesis of a novel series of 1,2-disubstituted cyclopentanes as small, potent potentiators of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors.
2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC(50) = 22.6 nM).
Shepherd
Timothy A
TA
NPS Allelix Corporation, 6850 Goreway Drive, Mississaugua, Ontario L4V 1V7, Canada. Shepherd_Timothy@Lilly.com
Aikins
James A
JA
Bleakman
David
D
Cantrell
Buddy E
BE
Rearick
John P
JP
Simon
Richard L
RL
Smith
Edward C R
EC
Stephenson
Gregory A
GA
Zimmerman
Dennis M
DM
Mandelzys
Allan
A
Jarvie
Keith R
KR
Ho
Ken
K
Deverill
Michelle
M
Kamboj
Rajender K
RK
D002460:Cell Line; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D018091:Receptors, AMPA / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D003517:Cyclopentanes; D018683:Excitatory Amino Acid Agents; D018091:Receptors, AMPA; D013449:Sulfonamides; C104724:glutamate receptor ionotropic, AMPA 4; C455282:propane-2-sulfonic acid (2-(4-iodophenyl)cyclopentyl)amide; D018698:Glutamic Acid