title: Adenosine kinase inhibitors. 2. Synthesis, enzyme inhibition, and antiseizure activity of diaryltubercidin analogues.
abstract: In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5'-amino-5'-deoxy- 5-iodotubercidin (1c) (IC50 = 0.0006 microM), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylamino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-arylamino-5-arylpyrrolo[2,3-d]pyrimidine bases were constructed and then glycosylated with appropriately protected alpha-ribofuranosyl chlorides using a phase-transfer catalyst. Several compounds exhibited potent activity in the rat MES seizure assay with ED50s < or = 2.0 mg/kg, ip, and showed relatively mild side effects.
authors.affiliation: Metabasis Therapeutics Inc, San Diego, California 92121, USA. ugarkar@mbasis.com
authors.forename: B G
authors.initials: BG
authors.lastname: Ugarkar
authors.forename: A J
authors.initials: AJ
authors.lastname: Castellino
authors.forename: J M
authors.initials: JM
authors.lastname: DaRe
authors.forename: J J
authors.initials: JJ
authors.lastname: Kopcho
authors.forename: J B
authors.initials: JB
authors.lastname: Wiesner
authors.forename: J M
authors.initials: JM
authors.lastname: Schanzer
authors.forename: M D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012640:Seizures / Q000188:drug therapy; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D000248:Adenosine Kinase; D014372:Tubercidin