(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.
A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC50S = 0.33 - 3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC50S = 600 - 23,000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (> 10,000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED50 = 26 +/- 1.5 mg/kg) and acute lethality (LD50[1 h] = 42 mg/kg) were observed at > 60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.
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