Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists

Abstract

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M (hM ICs<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma K=2.1, K=1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists.

Preparation of Unsymmetrical 1,2,4,5-Tetrazines via a Mild Suzuki Cross-Coupling Reaction

“…Carboni and Lindsey were the first to report that s -tetrazines could undergo cycloaddition reactions, and a number of groups have utilized this inverse demand Diels–Alder cycloaddition chemistry toward the synthesis of novel 3,6-substituted pyridazines, a heterocyclic motif found in myriad biologically active molecules . Contributions to this field by Boger and Sauer have allowed for the Carboni–Lindsey cycloaddition to find use in a number of elegant total syntheses, including Ningalin B, Lycogarubin C, and ent -(−)-Roseophilin .…”

Synthesis and anti‐proliferative activity studies of 2‐(2‐(trifluoromethyl)‐6‐(substituted)imidazo[1,2‐b]pyridazin‐3‐yl)‐N‐(substituted)acetamide derivatives

“…Recent literature review reveals that reactions involving hero atoms such as pyridazine were very advantageous in design of anti‐proliferative agents as they resemble many biomolecules. Piridazine and derivatives mainly act as potent and selective factor Xia inhibitors, inhibitors of TNF‐α production, potent PDE10a inhibitors, CNS penetrant pan‐muscarinic antagonists, Janus kinase (JAK) inhibitors . Piridazine in combination of other groups shows diversified activity like FXIa inhibitors …”

The Muscarinic Acetylcholine Receptor M5: Therapeutic Implications and Allosteric Modulation

“…It is important to note that these definitions are broad, and a full picture of allosteric modulation in a given system depends on a multitude of factors, , which are beyond the scope of this review. There are many examples in the literature describing nonselective muscarinic agonists and antagonists, − although the aim of this review is to focus primarily on those selective for M 5 . Examples of orthosteric M 5 antagonists will be discussed as well as the currently known structural classes of M 5 PAMs and NAMs.…”