作者: Blair, Harry C. ; Ray, Suravi ; Groschner, Klaus ; Jeon, Jaepyo ; Bacsa, Bernadett ; Geldenhuys, Werner ; Douglas, Aidan ; Nicewarner, Brady ; Tian, Jin Bin ; Zhu, Michael X. ; Berry, Kendyl ; Hall, Casey ; Soboloff, Jonathan ; McCall, Jamie L. ; Barnett, John B. ; Tyler, Kendall ; Liu, Siyao

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca 2+ -selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels. While ELP-004 minimally affected physiological RANKL-induced osteoclast maturation in murine bone marrow– and spleen-derived myeloid cells (BMSMCs) and human PBMC-derived cells, it potently interfered with osteoclast maturation driven by TNFα or LTB4. The contribution of TRPC channels to osteoclastogenesis was examined using BMSMCs derived from TRPC4 −/− or TRPC(1–7) −/− mice, again revealing preferential interference with osteoclastogenesis driven by proinflammatory cytokines. ELP-004 also reduced bone erosion in a mouse model of rheumatoid arthritis. These investigations reveal TRPC channels as critical mediators of inflammatory bone erosion and provide insight into the major target of ELP-004, a drug currently in preclinical testing as a therapeutic for inflammatory arthritis.

2024-08-01·Pharmacology Research & Perspectives

Preclinical evaluation of ELP‐004 in mice

Article

作者: Soboloff, Jonathan ; Söderberg, Björn C. G. ; Barnett, John B. ; McCall, Jamie L. ; Geldenhuys, Werner J. ; Gannett, Peter M. ; Robinson, Lisa J. ; Witt, Michelle R. ; Blair, Harry C.

AbstractThis study provides a detailed understanding of the preclinical pharmacokinetics and metabolism of ELP‐004, an osteoclast inhibitor in development for the treatment of bone erosion. Current treatments for arthritis, including biological disease‐modifying antirheumatic drugs, are not well‐tolerated in a substantial subset of arthritis patients and are expensive; therefore, new treatments are needed. Pharmacokinetic parameters of ELP‐004 were tested with intravenous, oral, and subcutaneous administration and found to be rapidly absorbed and distributed. We found that ELP‐004 was non‐mutagenic, did not induce chromosome aberrations, non‐cardiotoxic, and had minimal off‐target effects. Using in vitro hepatic systems, we found that ELP‐004 is primarily metabolized by CYP1A2 and CYP2B6 and predicted metabolic pathways were identified. Finally, we show that ELP‐004 inhibits osteoclast differentiation without suppressing overall T‐cell function. These preclinical data will inform future development of an oral compound as well as in vivo efficacy studies in mice.

1979-05-01·Journal of Agricultural and Food Chemistry

Structure-activity relationships for antidotes to thiocarbamate herbicides in corn

作者: Bunce, Nigel J. ; Stephenson, Gerald R. ; Bergsma, Michael D. ; Curry, James C. ; Makowski, Ruth I.

The antidote activity of 18 acetamides RCONR¹R² (R = CHCl₂, Me, CH₂Cl, Et, CCl₃; R¹ = H, Me, Et, Pr, or CH₂CH:CH₂; R² = Pr, CH₂CH:CH₂, Ph, 3,4-Cl₂C₆H₃, or cyclohexyl; R¹R² = cyclopentyl, cyclohexyl, morpholino, etc) and of Et N-ethyl-N-phenylcarbamate [1013-75-8] was tested for cycloate [1134-23-2], EPTC [759-94-4], vernolate [1929-77-7], pebulate [1114-71-2], molinate [2212-67-1], and butylate [2008-41-5], on corn in quartz sand nutrient culture or soil.The highest antidote activity against molinate in quartz sand was shown by N-dichloroacetylmorpholine [39205-49-7].In soil, the highest antidote activity was shown by R-25788 (N,N-diallyl-2,2-dichloroacetamide) [37764-25-3].The structural analogy between the herbicides and antidotes is discussed.Some of the compounds were prepared by known methods.

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