New Insight into the Structure-Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype†1 (EAAT1) Inhibitors UCPH-101 and UCPH-102.

In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R(1) and R(2) substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1'-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism.

Bioavailability Studies and in†vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype†1 (EAAT1) Inhibitor UCPH-102.

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood-brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg(-1) ) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 µm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 µm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg(-1) ) did not induce acute effects or any visible changes in behavior.

Synthesis of the tetracyclic core of berkelic acid using gold(I)-catalyzed hydroarylation and oxidative radical cyclizations.

A synthetic approach to the tetracyclic core of berkelic acid is reported using gold(I)-catalyzed intramolecular hydroarylation and oxidative radical cyclizations to effect the key ring-forming steps. The carboxylic acid was introduced via a late-stage palladium-catalyzed carbonylation to afford the core tetracycle with the correct relative stereochemistry for the natural product.

The Kulinkovich hydroxycyclopropanation reaction in natural product synthesis.

The Kulinkovich cyclopropanation reaction provides a flexible and convenient method for the synthesis of cyclopropanols. Together with the diverse chemistry of the cyclopropanol unit, it offers access to a wide range of functionalised unsaturated and saturated compounds. The successful use in the synthesis of natural compounds is outlined in this perspective.