RESUMO
A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
RESUMO
Methods to allow the clean preparation of oligosaccharides were investigated using techniques that do not require conventional column chromatography or an aqueous work-up. The route was designed to provide rapid access to oligosaccharides and is suitable for automation and parallel library formation. The research has focused on the glycosidations of a range of glycosyl acceptors with various selenophenyl glycosyl donors using iodine as an activator in the presence of DTBMP, a hindered organic base. Hydroxyl-containing contaminants were removed by scavenging with polymer-supported tosyl chloride.