Design, synthesis, and pharmacological evaluation of N-(3-carbamoyl-1H-pyrazol-4-yl)-1,3-oxazole-4-carboxamide derivatives as interleukin-1 receptor-associated kinase 4 inhibitors with reduced potential for cytochrome P450 1A2 induction.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical molecule in Toll-like receptor/interleukin-1 receptor signaling and an attractive therapeutic target for a wide range of inflammatory and autoimmune diseases as well as cancers. In our search for novel IRAK4 inhibitors, we conducted structural modification of a thiazolecarboxamide derivative 1, a lead compound derived from high-throughput screening hits, to elucidate structure-activity relationship and improve drug metabolism and pharmacokinetic (DMPK) properties. First, conversion of the thiazole ring of 1 to an oxazole ring along with introduction of a methyl group at the 2-position of the pyridine ring aimed at reducing cytochrome P450 (CYP) inhibition were conducted to afford 16. Next, modification of the alkyl substituent at the 1-position of the pyrazole ring of 16 aimed at improving CYP1A2 induction properties revealed that branched alkyl and analogous substituents such as isobutyl (18) and (oxolan-3-yl)methyl (21), as well as six-membered saturated heterocyclic groups such as oxan-4-yl (2), piperidin-4-yl (24, 25), and dioxothian-4-y (26), are effective for reducing induction potential. Representative compound AS2444697 (2) exhibited potent IRAK4 inhibitory activity with an IC50 value of 20 nM and favorable DMPK properties such as low risk of drug-drug interactions mediated by CYPs as well as excellent metabolic stability and oral bioavailability.

Therapeutic effects of interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 on diabetic nephropathy in type 2 diabetic mice.

Renal inflammation is a final common pathway of chronic kidney disease including diabetic nephropathy, which is the leading cause of end-stage renal disease and is associated with high cardiovascular risk and significant morbidity and mortality. Interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4) is a pivotal molecule for IL-1 receptor- and Toll-like receptor-induced activation of proinflammatory mediators. In this study, we investigated the renoprotective properties of IRAK-4 inhibitor AS2444697 in KK/Ay type 2 diabetic mice. Four-week repeated administration of AS2444697 dose-dependently and significantly improved albuminuria; hyperfiltration, as measured by creatinine clearance; renal injury, including glomerulosclerosis; tubular injury markers, including urinary N-acetyl-ß-D-glucosaminidase activity; and glomerular podocyte injury markers, including urinary nephrin excretion. In addition, AS2444697 attenuated plasma levels of proinflammatory cytokines, including IL-6; plasma levels of endothelial dysfunction markers, including intercellular adhesion molecule-1; and plasma levels and renal contents of oxidative stress markers. In contrast, AS2444697 did not significantly affect food intake or blood glucose levels. These results suggest that AS2444697 attenuates the progression of diabetic nephropathy mainly via anti-inflammatory mechanisms through inhibition of IRAK-4 activity under diabetic conditions and may represent a promising therapeutic option for the treatment of type 2 diabetic nephropathy.