Studies on a soft glycopyrrolate analog, SG-1.
A short-acting soft drug analog (SG-1) of glycopyrrolate (G) was developed by retrometabolic design in order to minimize systemic side effects and optimize the therapeutic index. SG-1,3-(1'-hydroxycyclopentyl)phenylacetoxy-1-methyl-1- methoxycarbonylpyrrolidinium bromide, was synthesized by: (a) esterification of phenylacetic acid with N-methyl-3-pyrrolidinol by DCC to obtain N-methyl-3-pyrrolidinyl phenylacetate; (b) reaction of lithium salt of above phenylacetates with cyclopentanone to obtain N-methyl-3-pyrrolidinyl 3-(1'-hydroxycyclopentyl)phenylacetate; and (c) quarternization with methyl bromoacetate in acetonitrile to give the designed product. To evaluate the pharmacological effect of SG-1, its mydriatic activity in rabbit eyes was compared to that of glycopyrrolate. At the pharmacodynamically equivalent doses (the lowest dose that induces the maximum response) of SG-1 (1%) and glycopyrrolate (0.1%), the mydriatic activities lasted for 5 and 100 h, respectively. Compared to glycopyrrolate, the intrinsic pupil dilation potency of SG-1 was lower (approximately 1/10th) but the duration of action was much shorter (< 1/20th) as SG-1 is susceptible to facile enzymatic hydrolysis/deactivation in the rabbit eyes. In vitro metabolism and stability investigations further supported this finding. In vitro half lives of SG-1 in rat plasma, blood, and 20% liver and lung tissue homogenates were 15.62, 53.86, 263.43, and 318.35 min, respectively. In human plasma and blood, half-lives were 19.93 and 88.32 min, respectively. SG-1 was relatively stable under acidic conditions (pH 5 and lower). SG-1 is a promising, clinically useful short acting anticholinergic.
Ji
F
F
Center for Drug Discovery, University of Florida, Gainesville, Florida, USA.
Wu
W M
WM
Bodor
N
N
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005732:Gangliosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D008297:Male; D009184:Mydriatics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats
D018678:Cholinergic Agents; D005732:Gangliosides; D007202:Indicators and Reagents; D009184:Mydriatics; C071655:sperm ganglioside 1