title: In-vivo activity of retinoid esters in skin is related to in-vitro hydrolysis rate.
abstract: BMS-181163 (4-acetamidophenyl retinoate, previously reported as BMY-30123), the acetamidophenyl ester of all-trans-retinoic acid (tRA), is topically active in various retinoid-sensitive animal models, but was recently shown to be ineffective for the treatment of acne in patients. To determine whether BMS-181163 functions as a prodrug of tRA in mice but not in man, the relative rates of ester hydrolysis in mouse and human skin homogenates were determined. In-vitro hydrolysis assays showed that BMS-181163 was substantially hydrolysed in mouse skin homogenates and minimally in human skin preparations. In addition, a series of phenyl esters of tRA and several known active synthetic retinoids (Ch-80: (E)-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 - propenyl] benzoic acid; CD-271: 6-[3-(1-adamantyl)-4-methyoxyphenyl]-2-naphthoic acid; and TTNPB: (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1- propenyl] benzoic acid) was prepared and hydrolysis rates and in-vivo (rhino mouse utriculi reduction) activities were compared. The hydrolysis rates of the six test retinoid phenyl esters, ranging from 0.06 to 2.0 h-1 were found to correlate with the in-vivo activity. Those esters (BMS-181163 and acetamidophenyl esters of Ch-80 and TTNPB) with a higher hydrolysis rate exhibited in-vivo activity only slightly lower than their parent free acid retinoids. In contrast, the three phenyl esters with a hydrolysis rate less than 0.3 h-1 were inactive in-vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Biochemical Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Buffalo, NY 14213, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: I M
authors.initials: IM
authors.lastname: Darling
authors.forename: K L
authors.initials: KL
authors.lastname: Yu
authors.forename: J E
authors.initials: JE
authors.lastname: Starrett
authors.forename: M M
authors.initials: MM
authors.lastname: Mansuri
authors.forename: G
authors.initials: G
authors.lastname: Whiting
authors.forename: K M
authors.initials: KM
authors.lastname: Tramposch
mesh_terms: D000068816:Adapalene; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D051379:Mice; D008812:Mice, Hairless; D009281:Naphthalenes / Q000494:pharmacology; D012176:Retinoids / Q000378:metabolism / Q000494:pharmacology*; D012444:Saccule and Utricle / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001565:Benzoates; D009281:Naphthalenes; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C077779:4-(acetylamino)phenylretinoate; D000068816:Adapalene; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; C098137:Ch 80