1370034-99-3Relevant academic research and scientific papers
Dual targeting of adenosine A2A receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones
St??el, Anne,Schlenk, Miriam,Hinz, Sonja,Küppers, Petra,Heer, Jag,Gütschow, Michael,Müller, Christa E.
, p. 4580 - 4596 (2013/07/19)
Blockade of A2A adenosine receptors (A2AARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)- N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A 2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A 2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD.
Benzothiazinones: A novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives
Gütschow, Michael,Schlenk, Miriam,G?b, Jürgen,Paskaleva, Minka,Alnouri, Mohamad Wessam,Scolari, Silvia,Iqbal, Jamshed,Müller, Christa E.
, p. 3331 - 3341 (2012/06/04)
2-(Acyl)amino-4H-3,1-benzothiazin-4-ones and related thienothiazinones were identified as structurally novel antagonists at adenosine receptors (ARs). 6-Methyl-2-benzoylamino-4H-3,1-benzothiazin-4-one (10d) was found to be a balanced AR antagonist with affinity for all human (h) subtypes (Ki hA1 65.6 nM; hA2A 120 nM; hA2B 360 nM; hA 3 30.4 nM), while in rat (r), 10d was a highly potent A 1-selective antagonist (rA1 7.7 nM; rA2A 546 nM; rA2B 679 nM, rA3 >10000 nM). 2-(4- Methylbenzoylamino)-4H-3,1-benzothiazin-4-one (10g) was found to be a potent antagonist at human A2A (68.8 nM) and A3 ARs (23.0 nM) with high selectivity versus the other human AR subtypes. In contrast to A 1 and A3 ARs, A2A and A2B ARs tolerated bulky 2-acyl substituents. tert-Butyl (4-oxo-4H-3,1-benzothiazin-2- ylcarbamoyl)benzylcarbamate (15g, Ki hA2B 186 nM; hA 2A 603 nM) and 4-(4-benzylpiperazine-1-carbonyl)-N-(4-oxo-4H-3,1- benzothiazin-2-yl)benzamide (15k, hA2A 69.5 nM; hA2B 178 nM) were highly selective versus the other AR subtypes. 2-Acylamino-3,1- benzothiazin-4-ones represent novel scaffolds suitable for the development of potent and selective AR antagonists for each of the four receptor subtypes.
