(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses.

(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.

Assay and purity evaluation of sunepitron hydrochloride by reversed-phase liquid chromatography using a reference standard composite.

A reference standard composite was prepared that contained the active pharmaceutical ingredient sunepitron and three potential impurities. This standard was characterized and used for concomitant quantitation of sunepitron and its potential impurities in samples of drug substance and drug product. This approach minimizes the number and quantity of reference standards which often are expensive to synthesize, characterize, and maintain. In addition, running assays becomes simpler because the number of reference standard solutions required for each assay is reduced. Reference standard composites can also be used for qualitative applications such as demonstrating system suitability or for retention times markers for process related impurities or degradants.

Validation of an HPLC method for the determination of CP-93,393 in CP-93,393-1 tablets.

A reversed-phase high performance liquid chromatographic (HPLC) assay developed for the CP-93,393-1 drug substance was adapted for use with CP-93,393-1 tablets. Using a novel experimental matrix, validation was performed to obtain linearity, reproducibility and recovery and to meet current regulatory requirements. Deviations in the sample preparation procedure were performed to demonstrate the ruggedness of the assay.