Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors

Abstract

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo-[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure−activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

Inducible knockout of Clec16a in mice results in sensory neurodegeneration

“…ISG15, a ubiquitin-like modifier that inhibits polyubiquitination and is involved in a post-translational modification process called ISGylation, has a role in autophagy by conjugating with other proteins to control clearance of protein aggregates 14 . Activation of ISIG15 occurs after cell stress 15 , when neuronal damage is present [16][17][18] , and is hypothesized to be a potential cause of defective mitophagy in neurodegenerative diseases 19 . ISG15 and ISGylation are implicated in the control of mitochondrial OXPHOS and recycling in bone marrow-derived macrophages 20 .…”

Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32

“…Physostigmine also mediates its antiproliferative activity on pancreatic cancer cells through the inhibition of p42/44 MAPK downstream of muscarinic receptors [ 56 ]. A substituted dihydropyridine ring on the imidazo[1,2- b ]pyridazine skeleton shows inhibition of the Janus kinase member, tyrosine kinase 2, leading to downstream reduction of interferon synthesis [ 88 ]. Similarly, an (R)-2-phenylpyrrolidine substituted imidazopyridazine shows potent inhibition of the tropomyosin receptor kinase (Trk) family of proteins responsible for driving tumorigenesis in various cancer types [ 89 ].…”

A Practical Synthesis of 1‐Azine‐pyridin‐2(1H)‐ones from Azine N‐oxides and Pyridin‐2(1H)‐ones under Mild Reaction Conditions

“…Nitrogen‐containing heteroaromatic compounds containing a pyridin‐2(1H)‐one motif have attracted considerable interest due to their numerous biological activities in medicinal chemistry, [1] such as anti‐HIV, [2] antitumor, [3] antioxidant, [4] and antiviral [5] . Meanwhile, in the field of organic chemistry, 1‐azine‐pyridin‐2(1H)‐ones are also widely employed as starting materials for the exploration of novel metal‐catalyzed C−H functionalization reactions [6] .…”