Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists

Abstract

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.

Striatal cholinergic interneurons regulate cognitive and affective dysfunction in partially dopamine‐depleted mice

“…Muscarinic receptors (M1–M5, mAChRs) are highly expressed within the striatum, particularly the M1 subtypes that are primarily expressed on medium spiny neurons (MSNs; Zhou, Wilson, & Dani, ; Kreitzer, ). The discovery of drugs acting on specific mAChR subtypes raised renewed interest in the modulation of striatal cholinergic signalling to alleviate basal ganglia disorders (Eskow Jaunarajs, Bonsi, Chesselet, Standaert, & Pisani, ; Michelle Lewis et al., ; Shen et al., ; Wess, Eglen, & Gautam, ). The imbalance between ACh and DA activity in the striatum is classically considered as central to the development of motor symptoms of PD (Di Chiara, Morelli, & Consolo, ; Pisani et al., ), although the two systems may also act in conjunction (Calabresi, Picconi, Tozzi, Ghiglieri, & Di Filippo, ; Parker, Lalive, & Kreitzer, ; Threlfell et al., ).…”

Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype

“…We have noted HTS DMSO stocks providing discrepancies with newly synthesized material on several occasions for various programs. 15 While a thienyl analog 14a proved slightly more potent than 10 , other aryl and heteroaryl congeners were far less potent or inactive. Cyclic alkyl moieties proved the most intriguing in this series, with the cyclohexyl congener 14g inactive, a cyclopentyl analog 14h weak (IC 50 > 10 μM), a cyclobutyl variant 14i affording submicrolar inhibition (IC 50 = 820 nM), and further contraction to a cyclopropyl derivative 14j provides inhibition comparable to cyclopentyl (IC 50 > 10 μM).…”

MAOS protocols for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines

“…15 Evaluation of 2 against M1–M5 indicated that 2 was indeed a selective M1 antagonist (M1 IC 50 = 23 μM, M2–M5 IC 50 >> 50 μM). Prior to this discovery there was only one other M1 selective small molecule antagonist, 16 and prior to its discovery, the only M1 selective antagonist was MT7, a 71 amino acid peptide toxin from the green mamba snake. 17 Encouraged by this result, we employed an iterative parallel synthesis approach, employing our new MAOS protocols, to rapidly develop structure–activity relationships in an attempt to improve the M1 antagonist potency while maintaining selectivity for M2–M5.…”