Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors

Abstract

Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.

Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study

“…Most of the known Syk inhibitor molecules have specific structural scaffolds, such as pyridine-2-carboxamide, pyrazin-8-amine, pyrimidine-8-carboxamide, pyrimidin-4-one, pyridazine-3-carboxamide, pyrimidine-5-carboxamide, (3 E )-3-(1 H -pyrrol-2-ylmethylidene)-1 H -indol-2-one and methylquinoline-4,6-diamine [15,18,19,20,21,22,23,24,25]. Tanshinone I, a phenanthrene derivative, has a simpler scaffold than those of known inhibitors.…”

Regioselective Synthesis, Molecular Descriptors of (1,5‐Disubstituted 1,2,3‐Triazolyl)Coumarin/Quinolone Derivatives and Their Docking Studies against Cancer Targets

“…Lucas et al. discovered that an ovality>1.44 is the indicator of non‐mutagenicity . In our case, ovality of all our products have been far above the threshold value and thus, our compounds are largely non‐mutagenic in nature.…”

Review: Basics of Drug Development in Rheumatology

“…Fortunately, many autoimmune disease targets, for example kinases such as BTK , Syk , and JAK , can be crystallized with small‐molecule inhibitors bound to them. In these cases, the lead identification and optimization can be enhanced and timelines potentially shortened.…”