Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma

Abstract

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((3,9,9)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3,4,9,9-hexahydro-1-cyclopenta[]quinolin-9-yl)amino)-4-oxobutanoic acid (, ) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.

π‐Lewis‐Base‐Catalyzed Asymmetric Vinylogous Umpolung Reactions of Cyclopentadienones and Tropone

“…Transformations of products.A sd epicted in Scheme 5a, the enone moiety remaining in the cycloadduct 3aenables the latent transformations to access more complex skeletons.The in situ generated 1,3-dipoles from reagent 28 [34] underwent highly diastereoselective [3+ +2] cycloaddition with 3a,affording the densely functionalized product 29 in an excellent yield with aretained ee value.Besides,the adduct 14 j from 1a and 13 j could be obtained in good results on alarger scale.After as eries of transformations,s ubstance 33,a safunctionalized analogue of highly active CRTh2receptor antagonists for the treatment of asthma, [35] was furnished in an enantioenriched manner (Scheme 5b). Moreover,ahighly diastereoselective allylic alkylation was carried out between product 16 a and carbonate 34 catalyzed by Pd(PPh 3 ) 4 ,a nd as ubsequent cycloaddition reaction of product 35 efficiently delivered the tricyclic framework 36 in an almost enantiopure form (Scheme 5c).…”

G Protein–Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action

“…The predicted homology models can yield comparable success rates in structure-based drug design with respect to the corresponding experimentally solved structures, especially for those that have been through refinement/selection with experimental data (Carlsson et al, 2011;Langmead et al, 2012;Mysinger et al, 2012;Lim et al, 2018). Compounds that have been discovered through structure-based drug design using GPCR homology models have also entered clinical trials (Langmead et al, 2012;Huang et al, 2018). Given the continuous rise of experimentally solved GPCR crystal structures, which also facilitate the generation of accurate homology structural models with chemically diverse ligands, it is anticipated that structure-based drug design methods will contribute increasingly to the GPCR drug development efforts, including those for asthma, to develop novel therapeutics with more desirable pharmacological properties.…”

Diastereo- and Enantioselective Synthesis of Eight-Membered Heterocycles via an Allylation/Ring Expansion Sequence Enabled by Multiple Catalysis

“…Cyclobuta­[ b ]­quinoline derivatives also exhibit important biological activities in medicinal chemistry . However, due to the high strain, it is difficult to construct this molecular framework, especially in a stereoselective version .…”