Kirk L. Olson, Melissa C. Holt, Fred L. Ciske, James B. Kramer, Paige E. Heiple, Margaret L. Collins, Carrie M. Johnson, Chi S. Ho, M. Inés Morano, Stephen D. Barrett

Cayman chemists develop a cell-active, PGD₂-competitive inhibitor with low nM affinity for H-PGDS that obeys the rule of five.

Highlights

• Potent, long-lived inhibition of hematopoietic prostaglandin D₂ synthase (H-PGDS) has potential as a therapeutic for a variety of inflammatory diseases including asthmatic anaphylaxis, mastocytosis, rheumatoid arthritis, and Duchenne muscular dystrophy.

• KMN-010034 was identified as a low nM inhibitor of H-PGDS from a targeted series of 20 compounds evaluated by a competitive binding assay, a direct binding assay, a kinetic inhibition assay, and a cell-based ELISA.
  

• This novel imidazole analog displays an increase in competition with glutathione (GSH) for the H-PGDS active site, compared to amide-linker analogs previously generated from pharma programs such as Sanofi's that are not competitive with GSH. The significance of this will be explored in a future publication.

Abstract

In seeking novel and potent small molecule hematopoietic prostaglandin D₂ synthase (H-PGDS) inhibitors as potential therapies for PGD₂-mediated diseases and conditions, we explored a series comprising multiple aryl/heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole “linker” between the pyrimidine or pyridine “core” ring and the “tail” ring system. We synthesized and screened twenty analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition assay, and a cell-based assay measuring suppression of LPS-induced PGD₂ stimulation. Amide analogs show ten-fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and good in vitro metabolic stability in both human and guinea pig liver microsomes.

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Cayman Products Related to This Research

HQL-79
Prostaglandin D Synthase (hematopoietic-type) FP-Based Inhibitor Screening Assay Kit - Green
Prostaglandin D₂ ELISA Kit

This work was conducted by the Cayman Medicinal Chemistry group who offers a fully integrated, multidisciplinary approach to developing a wide range of therapeutics.

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