Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors

Abstract

A novel series of biaryl amides was identified as RORγt inhibitors through core replacement of a starting hit 1. Structure−activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. Compounds 9a and 9g demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration. KEYWORDS: RORγt inhibitor, Th17 cell differentiation, biaryl amides, EAE, multiple sclerosis T helper (Th) 17 cells, a lineage of CD4 + effector T cells characterized by the production of IL-17A and IL-17F, are pathogenic in human autoimmune inflammatory diseases including multiple sclerosis (MS). 1−4 The presence of IL-17 was detected in MS lesions, and Th17 cells were observed in the infiltrations of mouse experimental autoimmune encephalomyelitis (EAE) central nervous system (CNS). 5,6 Differentiation and function of Th17 cells are controlled by the transcription factor retinoic acid receptor-related orphan receptor-gamma-t (RORγt). 7−9,11 It has been shown that the genetic deficiency of RORγt in mice severely impaired Th17 cell differentiation and conferred resistance to EAE. 10 RORγt inhibitors has potential utility in reducing the activity of Th17 cells and therefore can be developed as therapeutic agents for the treatment of Th17 cell mediated autoimmune diseases. 12−18 A few small molecule RORγt inhibitors have been reported in literature. 19 Digoxin, 20 SR1001, 21 and ursolic acid 22 were first reported to inhibit RORγt and ameliorate EAE in mice via intraperitoneal administration. Other small molecular RORγt inhibitors 23−31 were later disclosed. Recently, we reported discovery of thiazole ketone amides (e.g., 2) and thiophene ketone amides (e.g., 3) as novel RORγt inhibitors based on a high throughput screening (HTS) hit 1 (Figure 1). 32 These ketones, especially the thiophene ketones, showed good RORγt activities but were poorly orally bioavailable and lack of CNS penetration that is believed to be important for developing an effective oral MS drug. In this Letter, we report the discovery of novel biaryl amides as first potent, orally bioavailable, and CNS penetrant RORγt inhibitors, which demonstrated EAE in vivo efficacy dose dependently via oral administration.The lack of CNS penetration of thiazole/thiophene ketones was attributed to their ketone moiety as the nonketone thiazole amide 1 is CNS penetrant with a brain-to-blood ratio (Br/Bl) of 1.5 in a mouse CNS study (i.p., 2 mg/kg). 33 Encouraged by

Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

“…In addition, selected compounds in the series also demonstrated good metabolic stability. However, compared to the biaryl amide RORt inverse agonists recently disclosed, 33 the current thiazole ether compounds did have high Th17 cellular potency that is believed to be important for achieving in vivo efficacy in any Th17-mediated disease model. Further optimization of the series to improve Th17 cellular potency is undergoing.…”

Ternary complex of human RORγ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment

“…Humanized monoclonal antibodies against IL-17 have shown significant efficacies in psoriasis and psoriatic arthritis in human clinical trials (Langley et al 2014;Griffiths et al 2015). Now, small-molecule and oral inhibitors for RORc have been developed as an alternative therapy to injectable formulation of the biologics, which impose burdens on patients (Hirata et al 2015;Wang et al 2015b;Claremon et al 2016).…”

Th17 cells and their cytokines serve as potential therapeutic target in experimental autoimmune neuritis

“…RORγt-IN-1 is an agonist of RORγt that has displayed promising protective effects in animal models of multiple sclerosis (Wang et al, 2015). In our preliminary experiment, we have shown for the first (Wu, Wang, Liu, Zhu, & Zhang, 2016).…”

“…RORγt‐IN‐1 is an agonist of RORγt that has displayed promising protective effects in animal models of multiple sclerosis (Wang et al, ). In our preliminary experiment, we have shown for the first time that RORγt‐IN‐1 greatly improved EAN symptoms by reducing the severity of symptoms, delaying the onset of the first signs of EAN, and decreasing peak neurologic scores.…”

“…Of which, the control group EAN rats received an equal volume of PBS. The novel RORγt‐IN‐1 administration has been investigated in experimental autoimmune encephalomyelitis, and it can be concluded that significant therapeutic effect can be obtained at doses of 3 mg kg −1 day −1 (Wang et al, ). To determine whether this kind of RORγt inhibitor protected against the development of EAN, RORγt‐IN‐1 (at doses of 3 mg kg −1 day −1 ) was administered to experimental group rats via intragastric injection from day 0 to 28 p.i.…”