Synthesis and SAR of 4-(pyrazol-3-yl)-pyridines as novel c-jun N-terminal kinase inhibitors

Abstract

The design and synthesis of a novel series of c-jun N-terminal kinase (JNK) inhibitors is described. The development of the 4-(pyrazol-3-yl)-pyridine series was discovered from an earlier pyrimidine series of JNK inhibitors. Through the optimization of the scaffold 2, several potent compounds with good in vivo profiles were discovered.

Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives

“…To date, however, the development of specific small molecule inhibitors with high isoform selectivity for JNK3, especially against JNK1, is still a relatively untapped area as the three JNK isoforms share more than 90% sequence identity in the ATP pocket. Many published JNK3 inhibitors are also potent for JNK1, JNK2, and some inhibit p38α as well, because of their high degree of amino acid sequence similarity, which might lead to potential side effect profiles on immune and inflammatory systems. , Thus, developing isoform-specific JNK3 inhibitors as therapeutics has gained considerable interest over the past few years despite most reports being centered on pan-JNK inhibitors. ,− Our previous effort toward the development of isoform selective JNK3 inhibitors led to the identification of a class of aminopyrazole compounds. These aminopyrazole-based JNK3 inhibitors not only had high selectivity against p38α but also showed noticeable isoform selectivity against JNK1 (compound SR-4326, 18.5-fold, Figure ) .…”

Inhibitors of c-Jun N-Terminal Kinases: An Update

“…While compounds without substituents in the pyrazole C 4 -position (e.g., 18) were selective against p38 MAP kinase, a 4-fluorophenyl moiety ( 19) significantly enhanced JNK inhibition while also reducing p38 MAP kinase selectivity (Figure 11). 101 Owing to the structural similarity between 19 and pyridinylimidazole-derived p38α MAP kinase inhibitors, a similar binding mode accounting for the decrease in selectivity seems probable. 102 The brain/plasma ratio of 19 compared unfavorably to 15 and 16, and the overall PK profile was inferior as well.…”

Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1H-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors

“…2 fold. 30 A 5-chlorinated analogue of 9t (9 mm) was prepared in an attempt to encourage the horseshoe conformation and improve activity, but this instead resulted in a 4-fold potency loss, which may be explained by the chloro substituent obstructing coplanarity of the pyrimidine and pyrazole rings. Metabolic stability of this series continued to be poor, with typical half-life values of <20 min in mouse liver microsomes.…”