Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357

Abstract

The interleukin (IL)-23/T helper (Th)­17 axis plays a critical role in autoimmune diseases, and there is an increasing number of biologic therapies that target IL-23 and IL-17. The transcription factor retinoic acid receptor-related orphan nuclear receptor γt (RORγt) is important for the activation and differentiation of Th17 cells and thus is an attractive pharmacologic target for the treatment of Th17-mediated diseases. A novel series of pyrazinone RORγ antagonists was discovered through hybridization of two distinct screening hits and scaffold hopping. The series offers attractive potency and selectivity in combination with favorable druglike properties, such as metabolic stability and aqueous solubility. Lead optimization identified a clinical candidate, compound (S)-11 (BI 730357), for the treatment of autoimmune diseases.

Bounded integer model‐based analysis of psoriasis area and severity index in patients with moderate‐to‐severe plaque psoriasis receiving BI 730357

“…Given the late second concentration peak observed at 12–30 h after dose, the time course does not support the possibility of enterohepatic recycling, and colonic absorption may be more likely. BI 730357 has low water solubility, 21 and physiological based, 22 as well as compartmental 23 PK modeling of orally administered compounds with poor solubility has identified the sigmoid colon 22 and the intestine 23 as segments likely responsible for solubility‐limited late absorption.…”

Circadian Rhythms, Disease and Chronotherapy

“…These findings suggest the potential utility of ROR modulators as anti-diabetic and anti-obesity agents. On the other hand, multiple selective RORγ Inhibitors reduce T-helper cell 17 (Th17) responses as well as production of the proinflammatory cytokine IL-17, indicating the therapeutic potential of these molecules for autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, psoriasis, and inflammatory bowel disease (Cyr et al, 2016;Pandya et al, 2018;Cherney et al, 2020;Harcken et al, 2021;Meijer et al, 2021). Pharmacological inhibition of RORγ also exerts potent anti-tumor activity in in vitro and/or in vivo models of castration-resistant prostate cancer (J.…”

AZD0284, a Potent, Selective, and Orally Bioavailable Inverse Agonist of Retinoic Acid Receptor-Related Orphan Receptor C2

“…This was collected by filtration and washed with diethyl ether to give 18 (3.32 g, 73%) as a pale pink solid. HRMS: calculated for (C 21 (19). Following the procedure for the preparation of 18, 19 was obtained from 32b (1.14 g, 2.3 mmol, 0.16 mmol) and acetic acid (0.131 mL, 2.3 mmol) using T3P.…”

“…The large and mainly hydrophobic ligand-binding pocket (LBP) presents a challenge for the development of orally bioavailable small molecules. − Despite these difficulties, several orthosteric modulators with good pharmacokinetic properties for either oral or topical applications have been described. − Several of these molecules have also progressed into clinical trials, with one of them, VPT-43742, showing efficacy in psoriasis patients after oral administration over 4 weeks. − Recently, two classes of allosteric modulators, binding outside the canonical pocket of RORC2 have also been disclosed. − …”