Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein–coupled receptors (GPCRs) with DNA-encoded small-molecule libraries, we have discovered and characterized the first β2AR small-molecule positive allosteric modulators (PAMs)—compound (Cmpd)-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl)thio)benzamide] and its analogs. We used purified human β2ARs, occupied by a high-affinity agonist, for the affinity-based screening of over 500 million distinct library compounds, which yielded Cmpd-6. It exhibits a low micro-molar affinity for the agonist-occupied β2AR and displays positive cooperativity with orthosteric agonists, thereby enhancing their binding to the receptor and ability to stabilize its active state. Cmpd-6 is cooperative with G protein and β-arrestin1 (a.k.a. arrestin2) to stabilize high-affinity, agonist-bound active states of the β2AR and potentiates downstream cAMP production and receptor recruitment of β-arrestin2 (a.k.a. arrestin3). Cmpd-6 is specific for the β2AR compared with the closely related β1AR. Structure–activity studies of select Cmpd-6 analogs defined the chemical groups that are critical for its biologic activity. We thus introduce the first small-molecule PAMs for the β2AR, which may serve as a lead molecule for the development of novel therapeutics. The approach described in this work establishes a broadly applicable proof-of-concept strategy for affinity-based discovery of small-molecule allosteric compounds targeting unique conformational states of GPCRs.
Although copper-catalyzed amination of activated C(sp3)–H bonds through radical relay has been developed, amination of unactivated C(sp3)–H bonds is rare. Herein, copper-catalyzed intramolecular amination of remote unactivated C(sp3)–H bonds is reported. The reaction is conducted in a mild and effective manner with moderate to good yields, demonstrating broad tolerance toward various functional groups and exhibiting complete regio- and chemoselectivities. This innovation supplies novel synthetic pathways for the construction of saturated nitrogenated heterocycles.
Asymmetric allylic substitution of Morita-Baylis-Hillman (MBH) carbonates with less-nucleophilic phenols mediated by nucleophilic amine catalysis was successfully developed. A variety of substituted aryl allyl ethers were afforded with moderate to high yields with excellent enantioselectivities. The chiral MBH alcohol could be easily accessed from the corresponding aryl allyl ether.
Oxidative coupling of benzylamines to imines by molecular oxygen is efficiently realized in the presence of very low catalyst loadings of Co(II) β-tetrakis(trifluoromethyl)-meso-tetraphenylporphyrin. Due to the effect of four β-CF3 groups, the catalyst shows good selectivity and very high turnover number. The reaction is easily scaled up and may provide a convenient way to prepare many imines in large scale.
The asymmetric benzylation of methyl 4-oxo-3-piperidinecarboxylate has been investigated, and methyl (R)-1,3-dibenzyl-4-oxopiperidine-3-carboxylate (3c) was obtained by using a phase-transfer catalyst O-allyl-N-9-anthracenemethyl-cindexnine bromide (1k). This synthetic method has the advantages of cheap materials, mild reaction conditions and moderate enantioselectivity, and is useful for preparation of biologically active compounds containing a chiral 3-benzylpiperidine backbone.
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