Unanticipated Acyloxymethylation of Sumatriptan Indole Nitrogen Atom and its Implications in Prodrug Design

Abstract

Sumatriptan is a potent and selective 5-HT(1B) and 5-HT(1D )agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferentially at the indole nitrogen rather than at sulfonamide nitrogen, reflecting a difference either in product stability or in the nucleophilicities of the indole and sulfonamide anions. The hydrolysis of the corresponding N(1)-acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N(1)-Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N(1)-hydroxymethylsumatriptan at pH 1-13. Slow formation of the parent drug was observed only at high pH values. Hydrolysis of sumatriptan derivatives is slower in human plasma than in phosphate buffer and also generates N(1)-hydroxymethylsumatriptan rather than the parent drug. These results indicate that N(1)-acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.

The Role of Melatonin in the Treatment of Primary Headache Disorders

“…[16][17][18] Last, melatonin and indomethacin share an indole structure, which may make it effective in indomethacin-responsive disorders, 17 although this is a common structure in nature and appears in triptans and tetracylic ergolene derivatives, such as dihydroergotamine. 19,20 Melatonin's comparatively favorable side effect profile compared to indomethacin makes it a desirable treatment candidate. The side effects of melatonin are generally few and mild, even at high dosages; 17,21,22 daytime tiredness and dizziness are possible.…”

Structural Optimization of Quinolon-4(1H)-imines as Dual-Stage Antimalarials: Toward Increased Potency and Metabolic Stability

“…The mechanism of hydrolysis probably involves protonation of the 4-imino nitrogen atom, followed by alkyl C–N bond scission via an S N 1 mechanism, leading to the formation of amodiaquine and the corresponding secondary amide (Scheme ) . This mechanism is similar to that reported for the acid-catalyzed hydrolysis of N -acyloxymethyl − and N -amidomethyl prodrugs and involves the formation of an iminium ion intermediate, 4 , which can alkylate biomolecules, potentially contributing to toxicity . More recently, we have disclosed a library of N -alkyl-quinolon-4(1 H )-imines (e.g., 3 , Figure ), lacking the N -Mannich base moiety, as potent antiplasmodial agents that target the liver stage of infection .…”