Duchenne Muscular Dystrophy (DMD) is a rare but serious condition primarily seen in young males which is characterized by muscle tissue deterioration resulting from mutations in the dystrophin gene on the X chromosome. PGD2 is a major prostaglandin produced by mast cells and helps mediate the inflammatory responses of type 2 helper T lymphocytes (Th2 cells), mast cells, eosinophils, and dendritic cells and is a known inducer of chemotaxis and stimulates cytokine production. PGD2 has been implicated in allergic asthma, atopic dermatitis, niacin-induced vasodilation, and hair growth inhibition. PGD2 is produced by hematopoietic and/or lipocalin prostaglandin D synthases (hPGDS). A physchem property-centric high-throughput screen of 74K compounds against the hPGDS protein identified GSK’490A as a promising starting point for lead optimization. Early efforts focused on the quinazoline core which yielded improvements in cellular potency and permeability. An acid bioisostere approach and a rational design approach were subsequently applied to the piperidine ring leading to additional gains in both potency and permeability. This work will describe SAR efforts towards small molecule hPGDS inhibitors and synthetic methodology which enabled the preparation of functionalized piperidine building blocks.

Prostaglandin D synthase (hPGDS) inhibitors for the treatment of Duchenne muscular dystrophy

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