Øystein Rist

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Part 2 ☆

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.

Exploration of SAR features by modifications of thiazoleacetic acids as CRTH2 antagonists

The SAR features have been further explored for (2-benzhydryl-4-phenyl-thiazol-5-yl)acetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. The introduction of a nitrogen or a methyl substituent in the benzhydrylic position offer two alternative drugable scaffolds attractive for unsymmetrically substituted derivatives. An imidazole analogue lacks activity due to formation of a favored coplanar intramolecular hydrogen bond. The pyrimidine derivative 18 represents a potent and selective compound that will be subject to continued investigations.

Preparation and evaluation of sulfur-containing metal chelators

With a view to probe the structure and function of G-protein coupled receptors the synthesis of functionalized 8-mercaptoquinoline derivatives and 2-(2-pyridyl)thiophenol was achieved. A fluorescence-based method for determining the affinity of these metal chelators toward zinc ions was developed.

Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1

Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional antagonistic effect of 66 nM in a BRET and 12 nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27 microM in cAMP).

Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.

Synthesis and SAR studies of benzimidazole derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Focus to detune hERG inhibition

Melanin concentrating hormone receptor 1 (MCHR1) antagonists are potentially useful in the treatment of several CNS disorders such as obesity, stress, depression and anxiety. In a previous article, we have described a novel series of benzimidazoles as MCHR1 antagonists. These compounds showed good efficacy in obesity models but the lead compound also showed potent inhibition of hERG potassium channel. Described herein the medicinal chemistry attempts to reduce hERG inhibition while retaining MCHR1 antagonistic profile.

Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.