A novel series of positive modulators of the AMPA receptor: Discovery and structure based hit-to-lead studies

Abstract

Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.

AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

“…In the following paper [77] they described further optimization which led to (17) a compound which retains micromolar potency but with a pharmacokinetic profile suitable for further profiling.…”

“…Merck/Organon have published two consecutive articles [77,78], which describe the identification of a series of tetrahydrobenzthiophenes (16,17) in the first paper [77] they describe the initial optimization of a HTS hit to give a series of AMPAR modulators with micromolar potency (16) but with poor pharmacokinetics. In the following paper [77] they described further optimization which led to (17) a compound which retains micromolar potency but with a pharmacokinetic profile suitable for further profiling.…”

New regio-selective method of combinatorial synthesis of substituted thiophenes, thieno[3,2-b]pyridines and other heterocycles via combination of ‘domino’-type reactions

“…IR (KBr): 3356, 3260, 1632, 1616 cm -1 . 1 H NMR (300 MHz, DMSO-d 6 ): δ = 0.58-0.78 (m, 4H, (CH 2 ) 2 CH), 2.55 (m, 2H, SCH 3 ), 2.84 (m, 1H, (CH 2 ) 2 CH), 6.01 (s, 1H, C(6)H), 9.71 (br s, 1H, NH), 10.84 (br s, 1H, OH), 11.67 (br s, 1H, N(4)H). 13 Anal.…”

“…NMR 1 H and 13 C analyses were performed on "Bruker AM300" (300.13 and 75.47 MHz) spectrometer in DMSO-d 6 solution. High resolution mass spectra were obtained on "micrOTOF" mass-spectrometer.…”

“…1 Thiophenes, containing N-substituted amides in the three positions, have became an interest of several recent studies. 3 These molecules and their derivatives annulated with carbo-and heterocycles were shown as cannabinoid receptor ligands, 4 tumor growth inhibitors, 5 AMPA receptor modulators, 6 dihydroorthotetragenase inhibitors, 7 herbicides, 8 and mammalian hyperproliferative disorders agents. 9 Previously, we explored the synthesis of thieno [3,2-b]pyridines using thiophene derivatives as primary scaffolds.…”