Two distinct and scalable enantioselective approaches to the tricyclic indole (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo1,2-aindol-1-yl)acetate, an important synthon for a preclinical S1P1 receptor ...agonist, are reported. Route 1 employs a modified version of Smith’s modular 2-substituted indole synthesis as the key transformation. Route 2 involves a highly enantioselective CuH-catalyzed 1,4-hydrosilylation as the stereodefining step. Both routes can be performed without chromatography to provide multigram quantities of the tricycle in ≥98% ee.
The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT
receptor agonists are reported. An early lead containing a ...highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT
receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT
agonists were identified.
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•Novel chiral tricyclic tetrahydronaphthyridine-based tricyclic amines are described.•Compounds are valuable synthetic precursors to potent and selective 5-HT2C agonists.•Ring opening ...of fused bicyclic sulfamidate with dihalopyridinyllithiums.•Chemoselective intramolecular SNAr reaction.
Asymmetric syntheses of N-protected (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino1,2-a1,nnaphthyridines, advanced intermediates for the synthesis of highly potent and selective 5-HT2C agonists, are described. The key transformation involves ring opening of N-protected bicyclic sulfamidate (R)-hexahydro-3H-pyrazino1,2-c1,2,3oxathiazine 1,1-dioxide with (4-halo-2-fluoropyridin-3-yl)lithiums or (3-bromo-5-fluoropyridin-4-yl)lithium. In situ hydrolyses of the resultant sulfamic acids and subsequent intramolecular nucleophilic aromatic substitutions (SNAr) produce the enantiopure tricycles. The two step procedure represents new methodology for the stereoselective syntheses of tetrahydronaphthyridines.
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•Unique tricyclic amines with high degrees of molecular complexity are reported.•Ligands target centrally expressed GPCRs.•Two distinct asymmetric syntheses of ...tetrahydroquinoline-based tricyclic amines.•Dilithiation approach to enantiopure 2-substituted-1,2,3,4-tetrahydroquinolines.•Convergent route to tricyclic scaffold via coupling and intramolecular SNAr reaction.
Two distinct enantioselective approaches to (R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino1,2-aquinolines and (R)-1,2,3,4,5,5a,6,7-octahydro-1,4diazepino1,2-aquinolines, low MW tricyclic organic scaffolds with a high degree of molecular complexity, are described. The key transformation in route 1 is the lateral lithiation of an N-Boc-o-toluidine and dianion trap with (S)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane. An intramolecular SN2 cyclization then forms the optically pure tetrahydroquinoline core. Route 2 involves the coupling of (R)-2-(4-benzyl-1-(Boc)piperazin-2-yl)acetaldehyde or (R)-2-(4-benzyl-1-(Boc)-1,4-diazepan-2-yl)acetaldehyde with an aryllithium and a subsequent intramolecular SNAr reaction to form the tricycle. Both synthetic routes were valuable for preparing and identifying ligands targeting GPCRs expressed in the central nervous system (CNS).
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A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino1,2-a1,nnaphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a ...previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino1,2-a1,8naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
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A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in ...our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
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The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead ...containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of ...dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino1,2-a1,nnaphthyridines were identified as potent and selective agonists of the 5-HT
receptor. Optimizations performed on a previously reported ...series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino1,2-a1,8naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
