2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry

Scheme 28.
2.18. 2-ATs as JAK2 inhibitors
In 2014, Haidle and co-workers described the discovery of novel and selective trisubstituted thiophene inhibitors of the JAK2 enzyme for the treatment of polycythemia vera [92]. Toward systematic optimization, the authors rapidly replaced the urea fragment of the HTS hit 86 (Fig. 9) with a pyridyl substituent in an effort to reduce the PSA/HBD count of target samples. The pyridyl ring system was then held constant as physical and metabolic stability were optimized using an array of in vitro and in vivo assays. Eventually, 2-N-substituted thiophenes, such as compounds 87 and 88 (Fig. 9), displayed promising pharmacokinetic properties and showed PK/PD modulation of the JAK2 pathway in vivo. Actually, both compounds displayed in vivo activity; however, compound 88 (IC₅₀=2.0 µM) was more potent than compound 87 (IC₅₀=5.4 µM) and showed a longer-lasting effect. The discrepancy between the difference in their cell potencies (_~6-fold) and in vivo potencies (_~3-fold) may be related to differences in the free drug concentrations. Although the mouse plasma protein binding affinity for these compounds was not measured, the higher logD of compound 88 and lack of a basic amine implies that it has a lower free fraction in vivo.
Fig. 9.
2.19. 2-ATs as p38 kinase inhibitors
In 2011, Moffett and co-workers investigated various panels of 2-N-substituted thiophenes to discover highly selective, orally bioavailable p38 kinase inhibitors [93]. The authors used computational/virtual fragment-based drug design software and methods to design a novel p38 kinase inhibitor with outstanding selectivity. A thiophene derivative with 1,4-diazepane and 2,3-dichlorophenyl-urea fragments at the positions 2 and 3 (89, Scheme 29) exhibited low nanomolar potency in the p38 kinase assay (IC₅₀=0.022 µM), good cell potency (PBMC EC₅₀=0.34 µM; FFP–PBMC EC₅₀=0.86 µM) and high selectivity (>150-fold) in a 150 kinase panel. In addition, compound 89 showed oral bioavailability and suppressed TNF- and IL-1 expression in an animal efficacy model.