Yu_2008_J.Pharm.Biomed.Anal_46_75

Reference

Title : The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine - Yu_2008_J.Pharm.Biomed.Anal_46_75
Author(s) : Yu H , Li WM , Kan KK , Ho JM , Carlier PR , Pang YP , Gu ZM , Zhong Z , Chan K , Wang YT , Han YF
Ref : J Pharm Biomed Anal , 46 :75 , 2008
Abstract :

The lipophilicity and solubility profiles of bis(12)-hupyridone (B12H) and bis(7)-tacrine (B7T), two novel acetylcholinesterase inhibitors dimerized from huperzine A fragments and tacrine, respectively, were investigated over a broad pH range. Lipophilicity was assessed by both shake flask method with 1-octanol-water system and a reverse-phase HPLC system with methanol-water as mobile phase. The former method was used for determining the lipophilicities of the ionized forms (log D) of the dimers while the latter method was used for that of the neutral forms (log P). The log P values for B12H and B7T were found to be 5.4 and 8.2, respectively, indicating that the two dimers are highly lipophilic. The solubilities of both dimers were found to be affected by pH. The solubility of B12H was >1.41 mg/ml when the pH was <7, but <0.06 mg/ml when the pH was >8. The solubility of B7T was >0.26 mg/ml when the pH was <9, but <0.005 mg/ml when the pH was >12. The ionic strength of a solution could affect the solubilities considerably (11.16 mg/ml for B12H and 12.71 mg/ml for B7T in water; 2.07 mg/ml for B12H and 0.36 mg/ml for B7T in saline). The ionization constants (pK(a)) of the two dimers were determined by UV spectrophotometry. Both dimers were found to have two pK(a) values: 7.5+/-0.1 (pK(a1)) and 10.0+/-0.2 (pK(a2)) for B12H; and 8.7+/-0.1 (pK(a1)) and 10.7+/-0.4 (pK(a2)) for B7T. Furthermore, an in vivo pharmacological assay conducted in mice showed that a maximum AChE inhibition occurred 15 min after the single-dose and intraperitoneal administration of either dimer. This indicates that the two dimers may easily cross the blood-brain barrier. In summary, these physiochemical characteristics suggest that the two dimers may be promising candidates for the development of better drugs for Alzheimer's disease.

PubMedSearch : Yu_2008_J.Pharm.Biomed.Anal_46_75
PubMedID: 17931815

Related information

Inhibitor Bis7-tacrine

Citations formats

Yu H, Li WM, Kan KK, Ho JM, Carlier PR, Pang YP, Gu ZM, Zhong Z, Chan K, Wang YT, Han YF (2008)
The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine
J Pharm Biomed Anal 46 :75

Yu H, Li WM, Kan KK, Ho JM, Carlier PR, Pang YP, Gu ZM, Zhong Z, Chan K, Wang YT, Han YF (2008)
J Pharm Biomed Anal 46 :75