title: (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses.
abstract: (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.
authors.affiliation: Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Chenard
authors.forename: J
authors.initials: J
authors.lastname: Bordner
authors.forename: T W
authors.initials: TW
authors.lastname: Butler
authors.forename: L K
authors.initials: LK
authors.lastname: Chambers
authors.forename: M A
authors.initials: MA
authors.lastname: Collins
authors.forename: D L
authors.initials: DL
authors.lastname: De Costa
authors.forename: M F
authors.initials: MF
authors.lastname: Ducat
authors.forename: M L
authors.initials: ML
authors.lastname: Dumont
authors.forename: C B
authors.initials: CB
authors.lastname: Fox
authors.forename: E E
authors.initials: EE
authors.lastname: Mena
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016762:Genes, fos / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009410:Nerve Degeneration / Q000187:drug effects*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D016202:N-Methylaspartate; C095106:traxoprodil mesylate; C010739:ifenprodil