6-Aryl-quinazolines as novel GABAB receptor positive allosteric modulators.

The systemic use of GABAB orthosteric agonist baclofen might be limited due to its detrimental properties: sedation and motor impairment. In contrast, GABAB positive allosteric modulators produce less adverse effects. Using BHF-177 as a starting point, we found a new active scaffold: the 6-aryl-quinazoline scaffold. Further elaborating the scaffold, we identified several in vitro and in vivo active compounds.

Quinolinyl- and phenantridinyl-acetamides as bradykinin B1 receptor antagonists.

A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo.

hERG Optimization of Benzofuro-Pyridine and Pyrazino-Indole Derivatives as MCHR1 Antagonists.

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro-pyridine and pyrazino-indole scaffold was performed. We confirmed that fine-tuning lipophilicity and basic pKa by modifying the benzyl group and introducing different substituents on the aliphatic nitrogen sidechain decreases both hERG inhibition and metabolic clearance. We have succeeded to develop excellent in vitro parameters in the case of compounds 17 (4-[(5-chloropyridin-2-yl)methoxy]-1-[4-(2-hydroxyethyl)-8-oxa-4-azatricyclo[7.4.0.02 ,7 ]trideca-1(13),2(7),9,11-tetraen-11-yl]-1,2-dihydropyridin-2-one monohydrochloride) and 23 g (4-[(5-chloropyridin-2-yl)methoxy]-1-(1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)pyridin-2(1H)-one monohydrochloride), which can be considered as valuable tools for further pharmacological investigation.

Aspartic acid scaffold in bradykinin B1 antagonists.

Several novel bradykinin B1 receptor (B1R) antagonists were synthesized utilizing a new aspartic acid scaffold. This core is derived from the highly potent dihydroquinoxalinone scaffold published recently by researchers at Merck (Ha et al. Biochem. Biophys. Res. Commun. 2005, 331, 159-166). Despite the considerably limited chemical space of B1 antagonists, the synthesized compounds still showed significant biological activity. None of the four most potent compounds showed significant activity on the bradykinin B2 receptor (B2R), consequently they can be considered as valuable starting points for designing more potent and selective B1 antagonists. Furthermore, the synthesis of these aspartic acid derivatives is much simpler than that of the original Merck compounds suggesting efficient parallel synthesis approaches during their optimization. Docking known and novel B1 antagonists into the refined B1R homology model including the second extracellular loop (EC2) underlined the importance of this loop in ligand binding. Comparative binding mode analysis revealed that our novel compounds bind similar to the dihydroquinoxalinone template. Our results indicate that the rigid core of the dihydroquinoxalinone containing B1 antagonists is not crucial for maintaining B1 activity.

Novel bradykinin-1 antagonists containing a (1,2,3,4-tetrahydro-isoquinolin-1-yl)acetic acid scaffold.

A novel B(1) antagonist core was utilized and the effects of modification of its amide side chain on the biological activity were tested. The imino functional group of isoquinolin-1-ylacetic acid and its 6,7-dimethoxy variant was sulfonylated (4-toluenesulfonyl), while the acetyl side chain was converted to amides. Three of the synthesized compounds exhibited significant activity at the recombinant human B(1) receptors in binding tests and also in a functional assay.