Jerk Vallgarda

Discovery of a Potent, Orally Active 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor for Clinical Study: Identification of (S)-2-((1S,2S,4R)-Bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221)

Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.

Active site variability of type 1 11beta-hydroxysteroid dehydrogenase revealed by selective inhibitors and cross-species comparisons.

The NADPH-dependent enzyme type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) activates in a tissue-specific manner circulating pro-glucocorticoid hormones (cortisone in humans) to the 11beta-OH ligand (cortisol in humans), which is able to bind to its cognate receptor and regulate gene transcription. Modulation of this pre-receptor activation mechanism by selective enzyme inhibitors is a desirable goal in the treatment of insulin resistance and related metabolic disorders. Like most other hydroxysteroid dehydrogenases 11beta-HSD1 belongs to the evolutionarily conserved enzyme superfamily of short-chain dehydrogenases/reductases (SDR). The enzyme is anchored within the endoplasmic reticulum through an N-terminal transmembrane domain. In this study we aimed to characterize the active site of mammalian 11beta-HSD1 by determining primary structures from several mammalian lines (cat, hamster, cynomolgus, chimpanzee, dog) thus increasing substantially available sequence information, and allowing us to determine highly variable and constant parts within the primary structure. These regions were mapped to the recently determined three-dimensional structure and are mostly found around the substrate binding site. Furthermore we performed inhibition studies by using different series of inhibitors, comprising 11beta-HSD1 selective arylsulfonamidothiazoles and the unselective steroid-based compound carbenoxolone. The different arylsulfonamidothiazoles display distinct inhibition profiles versus the mammalian species tested, with several tight binding inhibitors for the human enzyme (Ki approximately 50 nM), intermediate for mouse, and weak or not binding inhibitors for rat and guinea pig (Ki>3 microM). Analysis of the inhibition mode reveals that the tight binding inhibitor BVT.528 is a competitive inhibitor for the human form, whereas the related compound BVT.2733 displays a mixed-type inhibition pattern versus the mouse enzyme. Taken together, this structure-activity study provides increased insight into active site complexity and catalytic mechanism of 11beta-HSD1, useful for further inhibitor design.

Stereoselectivity and generality of the palladium-catalysed cyclopropanation of α,β-unsaturated carboxylic acids derivatized with Oppolzer's sultam

A series of α,β-unsaturated carboxylic acids derivatized with camphorsultam 1 as a chiral auxiliary has been stereoselectively cyclopropanated. The selectivity of the reaction produces cyclopropanated products with the 1R, 2R absolute configuration as indicated by the optical rotations as well as by an X-ray structure determination. The temperature dependence of the reaction was studied with three substrates. The highest stereoselectivity was obtained at temperatures above 25 °C. Branching at the α- or β-carbons disfavours complete conversion, and electron-withdrawing substituents at these positions seem to prevent the reaction. The auxiliary was removed by using titanium(IV) isopropoxide in benzyl alcohol followed by alkaline hydrolysis of the intermediate ester. The potent 5-HT1A receptor agonist (1R,2S)-2-(2-hydroxyphenyl)-N,N-dipropylcyclopropylamine 13 was synthesized by this method.

Phenolic derivatives of 1,2-methano-N,N-dipropyl-1,2,3,4-tetrahydronaphth-2-ylamine. Structural hybrids of 2-aminotetralin-and phenylcyclopropylamine-derived 5-HT1A-receptor agonists

Abstract Three phenolic derivatives of 1,2-methano- N,N -dipropyl- 1,2,3,4-tetrahydronaphth-2-ylamine 6–8 were synthesized as structural hybrids of the potent 5-HT 1A -receptor agonist 8-OH-DPAT 1 and 2 related phenolic phenylcyclopropylamine 4 and 5 . The new compounds were assayed for 5-HT 1A -receptor affinity and efficacy in vitro . Hybrids 6 and 7 were considered to be inactive but 8 had a K i value of 130 nM for [ 3 H]-8-OH-DPAT labelled 5-HT 1A -receptors and produced an inhibition of the cAMP-production in the VIP-stimulated adenylyl cyclase assay. Thus, 8 is able to bind to and stimulate 5-HT 1A -receptors. The results are discussed in relation to a previously described 3-D model for 5-HT 1A -receptor agonists.