Synthesis and Biological Evaluation of Metabolites of 2‑<i>n</i>‑Butyl-9-methyl-8-[1,2,3]triazol-2-yl‑9<i>H</i>‑purin-6-ylamine (ST1535), A Potent Antagonist of the A_2A Adenosine Receptor for the Treatment of Parkinson’s Disease

The synthesis and preliminary in vitro evaluation of five metabolites of the A_2A antagonist ST1535 (<b>1</b>) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9<i>H</i>-purine (<b>2</b>) by selective C–C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A_2A receptor with affinities (<i>K</i>_i 7.5–53 nM) comparable to that of compound <b>1</b> (<i>K</i>_i 10.7 nM), thus showing that the long duration of action of <b>1</b> could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed

Synthesis of (<i>E</i>)‑8-(3-Chlorostyryl)caffeine Analogues Leading to 9‑Deazaxanthine Derivatives as Dual A_2A Antagonists/MAO‑B Inhibitors

A systematic modification of the caffeinyl core and substituents of the reference compound (<i>E</i>)-8-(3-chlorostyryl)­caffeine led to the 9-deazaxanthine derivative (<i>E</i>)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1<i>H</i>-pyrrolo­[3,2-<i>d</i>]­pyrimidine-2,4-(3<i>H</i>,5<i>H</i>)-dione (<b>17f</b>), which acts as a dual human A_2a antagonist/MAO-B inhibitor (<i>K</i>_i(A_2A) = 260 nM; IC₅₀(MAO-B) = 200 nM; IC₅₀(MAO-A) = 10 μM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A_2A antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti-Parkinson’s agents. A number of analogues of <b>17f</b> were synthesized and qualitative SARs are discussed. Two analogues of <b>17f</b>, namely <b>18b</b> and <b>19a</b>, inhibit MAO-B with IC₅₀ of 68 and 48 nM, respectively, being 5–7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC₅₀ = 334 nM)

ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors

A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ω-position. ST7612AA1 (<b>117</b>), selected as a drug candidate for further development, showed an in vitro activity in the nanomolar range associated with a remarkable in vivo antitumor activity, highly competitive with the most potent HDAC inhibitors, currently under clinical trials. A preliminary study of PK and metabolism is also illustrated