Structural characteristics of isoxazol-3-ol and isothiazol-3-ol, carboxy group bioisosteres examined by X-ray crystallography and ab initio calculations

Frydenvang, Karla; Matzen, Lisa; Norrby, Per-Ola; Sløk, Frank A.; Liljefors, Tommy; Krogsgaard‐Larsen, Povl; Jaroszewski, Jerzy W.

doi:10.1039/a700332c

Cited by 27 publications

(13 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A perspective drawing of the molecular structure of 9 ·HCl with atomic labeling is depicted in Figure . The absolute configuration was established to be R according to the procedure of Flack. , The bond lengths and angles are consistent with the general pattern of related compounds. ,− The isoxazole and furan rings are both planar within the limits of experimental errors, the inter planar angle being 10.4(1)°. The conformation of the cation is described by the selected torsion angles given in Table .…”

Section: Resultsmentioning

confidence: 78%

Heteroaryl Analogues of AMPA. 2. Synthesis, Absolute Stereochemistry, Photochemistry, and Structure−Activity Relationships

Falch¹,

Brehm²,

Mikkelsen³

et al. 1998

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

We have previously shown that (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA, 2] is a weak agonist at (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors, specifically activated by (S)-AMPA (1), whereas (S)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-4-isoxazolyl]propionic acid [(S)-2-Py-AMPA, 5] and (RS)-2-amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid (4) are potent AMPA agonists. On the other hand, (R)-APPA (3) and (R)-2-Py-AMPA (6) have been shown to be weak AMPA antagonists. We now report the synthesis of 2-Py-AMPA (7a) and the isomeric compounds 3-Py-AMPA (7b) and 4-Py-AMPA (7c) as well as the 7a analogues, (RS)-2-amino-3-[3-hydroxy-5-(6-methyl-2-pyridyl)-4-isoxazolyl]p ropion ic acid (7d) and (RS)-2-amino-3-[3-hydroxy-5-(2-quinolinyl)-4-isoxazolyl]propionic acid (7e). Furthermore, (RS)-2-amino-3-[3-hydroxy-5-(2-furyl)-4-isoxazolyl]propionic acid (2-Fu-AMPA, 7f) and its 5-bromo-2-furyl derivative (7g) were synthesized, and (S)-2-Fu-AMPA (8) and (R)-2-Fu-AMPA (9) were prepared by semipreparative chiral HPLC resolution of 7f. HPLC analyses and circular dichroism spectroscopy indicated the absolute stereochemistry of 8 and 9 to be S and R, respectively. This was confirmed by an X-ray crystallographic analysis of 9.HCl. In receptor binding (IC50 values) and rat cortical wedge electrophysiological (EC50 values) studies, 7c (IC50 = 5.5 +/- 0.6 microM; EC50 = 96 +/- 5 microM) was shown to be markedly weaker than 7a (IC50 = 0.57 +/- 0.16 microM; EC50 = 7.4 +/- 0.2 microM) as an AMPA agonist, whereas 7b,d,e were inactive. The very potent AMPA agonist effect of 7f (IC50 = 0.15 +/- 0.03 microM; EC50 = 1.7 +/- 0. 2 microM) was shown to reside exclusively in 8 (IC50 = 0.11 +/- 0.01 microM; EC50 = 0.71 +/- 0.11 microM), whereas 9 did not interact significantly with AMPA receptors, either as an agonist or as an antagonist. 8 was shown to be photochemically active and is a potential photoaffinity label for the recognition site of the AMPA receptors. Compound 7g turned out to be a very weak AMPA receptor agonist (IC50 = 12 +/- 0.7 microM; EC50 = 160 +/- 15 microM). None of these new compounds showed detectable effects at N-methyl-d-aspartic acid (NMDA) or kainic acid receptors in vitro. The present studies have emphasized that the presence of a heteroatom in the 2-position of the heteroaryl 5-substituent greatly facilitates AMPA receptor agonist activity.

show abstract

Section: Resultsmentioning

confidence: 78%

Heteroaryl Analogues of AMPA. 2. Synthesis, Absolute Stereochemistry, Photochemistry, and Structure−Activity Relationships

Falch¹,

Brehm²,

Mikkelsen³

et al. 1998

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…H atoms not involved in hydrogen bonding have been omitted. Symmetry codes are as indicated in Table 2. form, as in the crystal structure of the parent compound isoxazol-3-ol (Frydenvang et al, 1997). The molecular conformation is identical to that in the 5-and 7-carboxylated gaboxadol derivatives (Vogensen et al, 2004;Krogsgaard-Larsen et al, 1985).…”

Section: Tablementioning

confidence: 66%

Enantiotropically related polymorphs of gaboxadol hydrochloride

2013

View full text Add to dashboard Cite

Gaboxadol hydrochloride, also known as THIP hydrochloride (systematic name: 3-hydroxy-4,5,6,7-tetrahydro-1,2-oxazolo[5,4-c]pyridin-6-ium chloride), C6H9N2O2(+)·Cl(-), exists as two enantiotropically related polymorphs. Transformation between the polymorphs occurs in a single-crystal-to-single-crystal manner at 221 K, and the enthalpy of transformation from the high-temperature form to the low-temperature form is -0.7 kJ mol(-1). Single-crystal structures have been determined at 298 and 220 K. At 298 K, the structure is triclinic (space group P overline 1), with two formula units in the crystallographic asymmetric unit. At 220 K, the structure is monoclinic (space group I2/a), with one formula unit in the asymmetric unit. The structures contain identical hydrogen-bonded layers and the transformation between the polymorphs corresponds to a shift of adjacent layers relative to each other. The transformation is shown to be reversible by differential scanning calorimetry and variable-temperature powder X-ray diffraction.

show abstract

“…Isoxazolin-3-ones or isothiazolin-3-ones have been more studied than the corresponding 5-substituted derivatives. The spectroscopic data indicate that they exist as 3-hydroxy tautomers in solid state or in non-polar solvents, such as cyclohexane or ether, but more polar solvents resulted in a great contribution of the keto tautomers [6,21,59,60]. In the solid state these compounds form hydrogenbonded dimers 33.…”

Section: Tautomerismmentioning

confidence: 99%