Novel 2-imidazoles as potent, selective and CNS penetrant alpha1A adrenoceptor partial agonists.
A novel series of central nervous system (CNS) penetrant indane 2-imidazoles have been identified as potent, partial agonists of the alpha(1A) adrenergic receptor, having good selectivity over the alpha(1B), alpha(1D) and alpha(2) sub-types. A key structural motif to impart selectivity is a methylene spacer between the indane and a pendant substituent, which includes heterocycles, sulphones and ethers. Introduction of an ortho-halogen to this group led to a lowering of intrinsic efficacy (E(max)).
Roberts
Lee R
LR
Department of Chemistry, Pfizer Global Research and Development, Sandwich Labs, IPC432, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. lee.roberts@pfizer.com
Bryans
Justin
J
Conlon
Kelly
K
McMurray
Gordon
G
Stobie
Alan
A
Whitlock
Gavin A
GA
D058646:Adrenergic alpha-1 Receptor Agonists; D020816:Amino Acid Motifs; D002490:Central Nervous System / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D006219:Halogens / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
D058646:Adrenergic alpha-1 Receptor Agonists; D006219:Halogens; D007093:Imidazoles; D013449:Sulfonamides