3 research outputs found
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<sub>2A</sub> Adenosine Receptor for the Treatment of Parkinson’s Disease
The
synthesis and preliminary in vitro evaluation of five metabolites
of the A<sub>2A</sub> 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<sub>2A</sub> receptor with affinities (<i>K</i><sub>i</sub> 7.5–53 nM) comparable to that of compound <b>1</b> (<i>K</i><sub>i</sub> 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<sub>2A</sub> Antagonists/MAO‑B Inhibitors
A systematic modification of the caffeinyl core and substituents
of the reference compound (<i>E</i>)-8-(3-chlorostyryl)Âcaffeine
led to the 9-deazaxanthine derivative (<i>E</i>)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1<i>H</i>-pyrroloÂ[3,2-<i>d</i>]Âpyrimidine-2,4-(3<i>H</i>,5<i>H</i>)-dione (<b>17f</b>), which acts
as a dual human A<sub>2a</sub> antagonist/MAO-B inhibitor (<i>K</i><sub>i</sub>(A<sub>2A</sub>) = 260 nM; IC<sub>50</sub>(MAO-B)
= 200 nM; IC<sub>50</sub>(MAO-A) = 10 ÎĽM) and dose dependently
counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by
the oral route. The compound is the best balanced A<sub>2A</sub> 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 IC<sub>50</sub> of 68 and 48 nM, respectively,
being 5–7-fold more potent than the prototypical MAO-B inhibitor
deprenyl (IC<sub>50</sub> = 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