Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis

Abstract

Structure−activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 5−7. The hexahydropyrrolo[3,2-f ]quinoline series 5 (X = N, Y = ZCH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3, culminating in the discovery of 8e as a potent and selective RORγt inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis.

Direct chemical editing of Gram‐positive bacterial cell walls via an enzyme‐catalyzed oxidative coupling reaction

“…[ 2 ] However, genetic manipulation is technically demanding and falls short of the ability to engineer other nonproteinous biomolecules (e.g., sugars and lipids) or to functionalize bacteria with synthetic materials. [ 1a ] For these reasons, researchers have endeavored to develop a series of alternative approaches based on physical modification, including electrostatic adsorption, [ 3 ] lipid encapsulation, [ 4 ] and hydrophobic anchoring. [ 5 ] Designed as more facile and maneuverable tools, these strategies are capable of depositing different functional materials on bacterial cell surfaces, albeit in a less controllable manner.…”

Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists

“…IL-17A is a potent proinflammatory cytokine . Monoclonal antibody therapies that neutralize IL-17A (secukinumab and ixekizumab) or block its corresponding receptor (brodalumab) have been found to be highly efficacious in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. − Small molecule inverse agonists to RORC2 have been shown to inhibit in vitro production of IL-17A in Th17 cells and have demonstrated efficacy in preclinical models of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. − A wide diversity of structural chemistry has yielded potent RORC2 inverse agonists resulting in several oral clinical drug candidates ( 1 – 4 ) − as well as clinical candidates administered through topical delivery specific to the treatment of psoriasis ( 5 ), Figure . − The oral RORC2 inverse agonist vimirogant ( 1 ) was reported to reduce disease severity in a small cohort of patients with moderate-to-severe psoriasis . Topical administration of an RORC2 inverse agonist may offer advantages in patient convenience and safety; however, despite such agents having apparently entered into clinical trials, to date, a similar report of early clinical efficacy has not appeared.…”