Discovery of N-substituted 7-azaindoline derivatives as potent, orally available M1 and M4 muscarinic acetylcholine receptors selective agonists

Photosensitized Intramolecular [2+2] Cycloaddition of 1H-Pyrrolo[2,3-b]pyridines Enabled by the Assistance of Lewis Acids

“…The triplet energy (E T ) of 3 is reported as E T = 67.3 kcal/mol. 23 Though we could not find E T of N-acyl-1Hpyrrolo [2,3-b]pyridines in the literature, energy transfer from 3 [3]* to both coordinated and noncoordinated substrates seems possible because a similar compound can be sensitized by an Ir photocatalyst, whose E T is 61.2 kcal/mol. 17 We found that the addition of Mg(OTf) 2 hardly affected the reaction of compound 7 with an alkenyl linker at the 3-position, whose conformation is not under the influence of the pyridine nitrogen, and the conformational fixation was not necessary (Scheme 4), though the possibility that the 5-exo-cyclization of 7 is easier than the corresponding 6-exo-cyclization of 1a could not be ruled out.…”

“…1 H -Pyrrolo­[2,3- b ]­pyridine (7-azaindole) derivatives are common structural motifs in many bioactive natural products, useful pharmaceuticals, and agrochemicals. − On the other hand, in conjunction with a recent trend in drug discovery, i.e., “escape from flatland” concept, conformationally restricted small-ring-fused compounds have also attracted much attention in modern medicinal chemistry. , Cyclobutane-fused compounds form an important core of such compounds because of the balance they strike between the inherent rigidity of a small-ring compound and the greater stability toward ring-opening reactions compared with cyclopropane derivatives . Accordingly, novel cyclobutane-fused 1 H -pyrrolo­[2,3- b ]­pyridine frameworks may be of interest in bioactive screening for new pharmaceutical candidates.…”

Discovery and Development of Muscarinic Acetylcholine M₄ Activators as Promising Therapeutic Agents for CNS Diseases

“…24 28) As expected, M 4 mAChR activators have also been found to possess antipsychotic effects in behavioral tests for psychosis. These compounds reversed psychostimulant-or NMDA receptor antagonist-induced locomotor hyperactivity, as well as psychostimulant-induced disruption of PPI [29][30][31][32][33][34][35][36][37][38] in rodents. In a rat electroencephalogram study, the M 4 mAChR positive allosteric modulator (PAM) VU0467154, like clozapine, reversed MK-801-induced elevations in high frequency gamma power, which is consistent with their antipsychotic activities.…”

Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres

“…Achieving subtype selectivity for agonists has proven to be highly challenging, due to the highly conserved orthosteric binding site across subtypes. Thus far, only a few mAChR agonists with various degrees of selectivity have been reported, including M1-selective agonists such as compounds 1 and 2 , , M1 and M4 dual agonists 3 and 4 , and M4-preferred agonists 5 , as illustrated in Figure . Modification of the M1/M4 dual agonist 3 , such as through introduction of a quarternary methyl group at the 4-position of piperidine, led to the highly M4 mAChR selective agonist 6 , which exhibited little agonist activity against M1–M3 and M5.…”

“…Chemical structures of representative mAChR agonists. Nonselective mAChR agonists: acetylcholine, iperoxo, and xanomeline; M1-selective agonists: 1 (AC-42) and 2 (GSK1034702); M1/M4 dual agonists: 3 (derivative 1 from ref ) and 4 (HTL9936); M4-preferred agonist: 5 (example from WO2017021728 A1); and M4-selective agonist 6 (compound 1 from ref ).…”