James M. Rinker

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.

Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors†

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

Synthesis and evaluation of azapeptide-derived inhibitors of serine and cysteine proteases

Abstract Azapeptide analogues ii of the α-halomethyl ketones i were synthesized and evaluated as potential inhibitors of serine and cysteine proteases. Inhibitors ii discriminate between the two classes of protease, demonstrating selectivity for cysteine proteases. Azaglycines 1–3 and 5 displayed time-dependent inactivation (kobs/[I] = 200–1500 M−1s−1) of cathepsin B and calpain.

3-chloro-4-carboxamido-6-arylpyridazines as a non-peptide class of interleukin-1β converting enzyme inhibitor

Abstract The 3-chloro-4-carboxamido-6-arylpyridazines are a novel class of interleukin-1β converting enzyme (ICE) inhibitor. These agents are irreversible inhibitors with pyridazine 23 possessing a k obs [I] = 355 M−1s−1. A structure-activity relationship for this non-peptide class of compounds and the putative mechanism for irreversible inactivation are described.