Rational design of a drug for Alzheimer's disease with cholinesterase inhibitory and neuroprotective activity

The rate and duration of inhibition of recombinant human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE) by nine N-methyl,N-alkyl derivatives of (R)–3-prop-2-ynylamino-indan, designed as potential treatment of Alzheimer's disease, was obtained from measurement of the carbamylation ki and decarbamylation k3 rate constants. This also provided information about the rate of formation of the leaving group, 6-OH-(R)–3-prop-2-ynylamino-indan, designed as an MAO-B inhibitor with neuroprotective activity. The N-dimethyl derivative had the highest ki of the alkyl derivatives. Substitution of one N-methyl by N-ethyl resulted in a 14-fold decrease in ki and 28-fold decrease in k3. A progressive increase in ki occurred as the length of the alkyl chain progressed from propyl to n-hexyl and cyclo-hexyl, with relatively little or no increase in k3. Higher ki values than that of the dimethyl analogue were obtained with the N-aryl substitutes, N-phenyl and N-methoxy-phenyl. Six of the compounds had much higher ki values for BuChE than AChE, but the N-cyclo-hexyl and N-methoxy-phenyl compounds were inactive. However, an inverse relation was found between ki and the degree of brain AChE inhibition ex vivo after parenteral administration of the compounds in rats. This could have resulted from more rapid hydrolysis of the compounds with high ki values by esterases in blood and liver. Only the N-ethyl and N-propyl derivatives showed AChE and BuChE inhibitory activity in vivo of a suitably slow onset and long duration, together with MAO-B inhibition.