Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534

Abstract

The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases, and biologics targeting IL-23 and IL-17 have shown significant clinical efficacy in treating psoriasis and psoriatic arthritis. JNJ-61803534 is a potent RORγt inverse agonist, selectively inhibiting RORγt-driven transcription versus closely-related family members, RORα and RORβ. JNJ-61803534 inhibited IL-17A production in human CD4+ T cells under Th17 differentiation conditions, but did not inhibit IFNγ production under Th1 differentiation conditions, and had no impact on in vitro differentiation of regulatory T cells (Treg), nor on the suppressive activity of natural Tregs. In the mouse collagen-induced arthritis model, JNJ-61803534 dose-dependently attenuated inflammation, achieving ~ 90% maximum inhibition of clinical score. JNJ-61803534 significantly inhibited disease score in the imiquimod-induced mouse skin inflammation model, and dose-dependently inhibited the expression of RORγt-regulated genes, including IL-17A, IL-17F, IL-22 and IL-23R. Preclinical 1-month toxicity studies in rats and dogs identified doses that were well tolerated supporting progression into first-in-human studies. An oral formulation of JNJ-61803534 was studied in a phase 1 randomized double-blind study in healthy human volunteers to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated in single ascending doses (SAD) up to 200 mg, and exhibited dose-dependent increases in exposure upon oral dosing, with a plasma half-life of 164 to 170 h. In addition, dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood was observed, demonstrating in vivo target engagement. In conclusion, JNJ-61803534 is a potent and selective RORγt inhibitor that exhibited acceptable preclinical safety and efficacy, as well as an acceptable safety profile in a healthy volunteer SAD study, with clear evidence of a pharmacodynamic effect in humans.

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

“…In summary, we have further optimized our series of RORC2 inverse agonists, represented by compound 2, resulting in an isoindoline-based series, from which the clinical candidate AZD0284 (20) was identified. Optimization concentrated on further improvement of cell-based potency and pharmacokinetic properties with the aim of reducing the predicted efficacious clinical dose.…”

“…Amine 32d (270 mg, 0.51 mmol) was coupled with acetic acid (0.029 mL, 0.51 mmol) in DCM (6 mL) using HATU (215 mg, 0.56 mmol) and DIPEA (0.27 mL, 1.54 mmol). The crude product was purified by flash C18-flash chromatography (0 to 30% MeCN in water) to afford 24 (20 13 C NMR (126 MHz, DMSO-d 6 , only major rotamer reported) δ 22.41, 53.26, 55. 47, 58.12, 66.61, 119.64, 123.42, 123.87, 125.96, 127.99, 128.16, 139.51, 140.66, 140.96, 142.11, 168.18, 169.44 (signals for CCF 3 and C-OH could not be assigned).…”

“…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. − …”

An inhibitor of RORγ for chronic pulmonary obstructive disease treatment

“…Based on clinical trial results of a safe and well tolerated antagonist of RORγ, VTP-43742 showed efficacy in patients with psoriasis in a phase II study (NCT02555709) indicating its anti-inflammatory role. Similarly, oral JNJ‑61803534SHR168442 13 inhibitor and the topical application of SHR168442 14 for psoriasis are additional examples of the anti-inflammatory benefit of RORγ inhibition. Thus it is hypothesized that a RORγ antagonist could be a novel therapeutic target for COPD by regulating IL-17 mediated inflammation.…”

Cathodic Regioselective Coupling of Unactivated Aliphatic Ketones with Alkenes

“…Tertiary alcohol derivatives have attracted long-term attention due to their widespread presence in natural products, pharmaceuticals, and synthetic intermediates . In particular, the 2-hydroxyisopropyl moiety is a structural feature in many drugs and bioactive molecules of clinical interest, such as the leukemia treatment drug omacetaxine mepesuccinate (Synribo), IRAK4 inhibitors (BAY1834845), reversible inhibitors of Bruton’s tyrosine kinase (BTK) (BMS-986142), and so on (Figure ).…”