title: Amine prodrugs which utilize hydroxy amide lactonization. II. A potential esterase-sensitive amide prodrug.
abstract: In an effort to develop esterase-sensitive pro-prodrugs for amines, an amide derivative of 3-(2'-acetoxy-4',6'-dimethylphenyl)-3,3- dimethylpropionic acid (4-methoxyaniline amide 8) was synthesized and its stability investigated. This esterified hydroxy amide was found under all conditions to degrade via a two-step process initiated by acetyl ester hydrolysis generating the hydroxy amide intermediate 9a. The lactonization of this intermediate 9a in the second step resulted in the formation of 4-methoxyaniline (10) and 4,4,5,7-tetramethyl-3,4-dihydrocoumarin (1a). The pro-prodrug 8 was observed to possess the following half-lives at 37 degrees C under various conditions: 4030 min in phosphate buffer (50 mM, mu = 0.15) fixed to pH 7.4, 11.9 min in the same buffer containing a porcine liver esterase, 53.7 min in plasma, and 475 min in plasma containing diisopropylfluorophosphate. These results suggest that in a biological milieu the ester hydrolysis will occur by the enzymic hydrolysis rather than the chemical hydrolysis and that the enzymic hydrolysis of 8 in plasma is due, in part, to the action of serine-dependent esterases.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
authors.forename: K L
authors.initials: KL
authors.lastname: Amsberry
authors.forename: A E
authors.initials: AE
authors.lastname: Gerstenberger
authors.forename: R T
authors.initials: RT
authors.lastname: Borchardt
mesh_terms: D000577:Amides / Q000097:blood / Q000138:chemical synthesis* / Q000378:metabolism; D000588:Amines / Q000008:administration & dosage*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004950:Esterases / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000097:blood / Q000138:chemical synthesis* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D013552:Swine
chemical_list: D000577:Amides; D000588:Amines; D007783:Lactones; D011355:Prodrugs; D004950:Esterases