Discovery of pyridachlometyl: A new class of pyridazine fungicides.

Pyridachlometyl is a unique pyridazine fungicide with a novel mode of action. Herein, we describe the pathway for the invention of pyridachlometyl. First, we identified a diphenyl-imidazo[1,2-a]pyrimidine as our proprietary lead with potent fungicidal activity. Then, aiming to simplify the chemical structure, we applied judicious estimations to explore monocyclic heterocycles as pharmacophores. This enabled the identification of a novel class of tetrasubstituted pyridazine compounds with potent fungicidal activity, likely retaining the same mode of action as the aforementioned compounds. The findings indicated bioisosteric similarity between diphenyl-imidazo[1,2-a]pyrimidine and pyridazine. Further structure-activity and mammalian safety investigations of pyridazine compounds resulted in the discovery of pyridachlometyl as a candidate for commercial development.

Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease.

The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.

Initial repertoire of anti-(4-hydroxy-3-nitrophenylacetyl) antibodies as potential donors for effective affinity maturation.

We previously found that there are two distinct antibody (Ab) maturation pathways for the immune response of C57BL/6 mice to 4-hydroxy-3-nitrophenylacetyl (NP), one involving Abs with high evolvability (group-H) and the other involving Abs with low evolvability (group-L). Commitment to whichever pathway is followed pre-determined in B cells at an early developmental stage. Candidates for the group-L or -H pathway are thus expected to pre-exist in the initial repertoire of the immune response. In the present study, we examined the initial Ab repertoire from the viewpoint of the latent potential of these Abs for effective affinity maturation. At first, we prepared anti-NP B cell hybridomas at 1 week postimmunization. Although the diversity of the obtained repertoire was maintained mainly by the third complementarity determining region of the heavy chain (CDR-H3), their changes in the near UV circular dichroism resulting from NP-binding allowed for classification into three groups according to the same rules applied in the pathway classification of the maturated Abs. This suggested that the innate structural properties of CDR-H3 were conserved throughout maturation. In other words, in exploring the structure of CDR-H3, it is possible to distinguish the latent potentials of Abs in effective affinity maturation even those making up the initial Ab repertoire. We then examined an artificially designed group-H Ab prototype and found its NP-binding ability sufficient for engagement in the initial repertoire. The question arose here as to why the majority of the actual initial repertoire consisted of the group-L ancestors regardless of their middling NP-binding affinity, which called for further discussion from the viewpoint of the dynamics possibly shaping the repertoire.

Synthesis and fungicidal activity of 1-(alpha-tert-butylcinnamoyl)imidazoles.

Several 1-(alpha-tert-butylcinnamoyl)imidazoles were prepared to examine their fungicidal activity. The (Z)-4-chlorocinnamoyl derivative was prepared from (anti)-2-tert-butyl-3-(4-chlorophenyl)-3-hydroxypropanoic acid by treating with 1,1'-carbonyldiimidazole and a subsequent beta-elimination reaction at an elevated temperature. The (Z)-isomer of the 4-chlorocinnamoyl derivative showed good fungicidal activity against Erysiphe graminis and Botrytis cinerea in pot tests, whereas the corresponding (E)-isomer derived from the (Z)-isomer through photoisomerization was much less active.