Tina Marie Morwick

Pim kinase inhibitors: a survey of the patent literature

Importance of the field: Pim kinases have recently emerged as targets of interest in oncology and immune regulation. Ongoing studies have identified a role for these proteins in cell survival and proliferation, both functionally and mechanistically, and overexpression has been observed in a number of human cancers and inflammatory states. Areas covered in this review: This report reviews the patent literature for Pim kinase inhibitors identified from a search of the Thomson patent databases from 1970 through July 2009. Full analyses are provided for publications reporting Pim kinases as primary targets, and a cursory description is given for those disclosing Pim as one of a limited number of secondary targets. What the reader will gain: Readers will gain an overview of the various inhibitor series including coverage, potency, selectivity, protein binding features and therapeutic focus, and an appreciation for which scaffolds and structural features have been most highly exploited. Take home message: A greater understanding of pathological mechanisms for Pim kinases has stimulated the recent development of a variety of inhibitor classes with one compound advancing into the clinic earlier this year. Ongoing studies will help define applications for these inhibitors in the treatment of Pim-associated human diseases.

Discovery and SAR of novel Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK).

The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.

The discovery of thienopyridine analogues as potent IκB kinase β inhibitors. Part II

An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.

Isoquinolinone synthesis by SNAr reaction: a versatile route to imidazo[4,5-h]isoquinolin-9-ones

Abstract Reaction of 2-chlorobenzonitriles with β-ketoesters in an S N Ar reaction, followed by cyclization in acid provides a versatile route to isoquinolones. Starting from 2,6-dichloro-3-nitrobenzonitrile 7 , sequential displacement of the chlorines by an amine and a β-ketoester leads to imidazo[4,5- h ]isoquinolin-9-ones 1 , a new class of kinase inhibitor.