title: 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.
authors: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors: Matthew C
authors: MC
authors: Lucas
authors: Niala
authors: N
authors: Bhagirath
authors: Eric
authors: E
authors: Chiao
authors: David M
authors: DM
authors: Goldstein
authors: Johannes C
authors: JC
authors: Hermann
authors: Pei-Yuan
authors: PY
authors: Hsu
authors: Stephan
authors: S
authors: Kirchner
authors: Joshua J
authors: JJ
authors: Kennedy-Smith
authors: Andreas
authors: A
authors: Kuglstatter
authors: Christine
authors: C
authors: Lukacs
authors: John
authors: J
authors: Menke
authors: Linghao
authors: L
authors: Niu
authors: Fernando
authors: F
authors: Padilla
authors: Ying
authors: Y
authors: Peng
authors: Liudmila
authors: L
authors: Polonchuk
authors: Aruna
authors: A
authors: Railkar
authors: Michelle
authors: M
authors: Slade
authors: Michael
authors: M
authors: Soth
authors: Daigen
authors: D
authors: Xu
authors: Preeti
authors: P
authors: Yadava
authors: Calvin
authors: C
authors: Yee
authors: Mingyan
authors: M
authors: Zhou
authors: Cheng
authors: C
authors: Liao
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D019295:Computational Biology; D003198:Computer Simulation; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D016296:Mutagenesis / Q000187:drug effects; D009152:Mutagenicity Tests; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013154:Spleen / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000577:Amides; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011505:Protein-Tyrosine Kinases