SAR Exploration Guided by LE and Fsp³: Discovery of a Selective and Orally Efficacious RORγ Inhibitor

Abstract

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp 3 carbon atoms (Fsp 3 ), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.KEYWORDS: Th17, immunological diseases, nuclear receptor, RORγ, ligand efficiency (LE), fraction of sp 3 carbon atoms (Fsp 3 )T wo decades after the discovery of Th1 and Th2 cells, a third subset of T helper cells called Th17 cells was identified and has drawn considerable attention since it was suggested to play a central role in the pathogenesis of various autoimmune diseases such as psoriasis and rheumatoid arthritis. 1,2 Among several regulatory pathways in which Th17 development and function are involved, the one regulated by the nuclear receptor RORγ appears to be crucial for controlling the differentiation and function. 3 Given its validity as an emerging drug target for treatment of immunological diseases, many research groups have made significant efforts in the discovery of RORγ modulators in recent years. 4−19 Since starting our RORγ inhibitor program in 2003, we discovered several structurally diverse hits after a HTS campaign. 20 From these hits we selected compound 1 as the first hit-to-lead series for optimization. In addition to being reasonably potent against RORγ (hLUC EC 50 = 1.7 μM, FRET EC 50 = 0.85 μM), compound 1 also demonstrated >20-fold selectivity over five nuclear receptors (hRORα, hFXR, hRXRα, hPR, and hPPARγ) and was structurally unique in comparison to other nuclear receptor modulators. 16−18 However, this compound has several drawbacks. For example, the microsomal stability in liver microsomes is poor with only 18% remaining at 10 min in human liver microsomes. It also has a modest time-dependent human CYP3A4 inhibition (IC 50 = 4 μM) probably due to some reactive metabolites formed by the oxidation of 1. The ligand efficiency is only 0.25, far below the literature consensus value (0.30) for a drug-like molecule. 21 The concept of ligand efficiency (LE) was first introduced by Kuntz 22 and is widely accepted as a reliable index of drug-like qualities. 23 Improvement of LE inevitably results in lower molecular weight and higher potency. We reasoned that a strategy of increasing LE and lowering the lipophilicity should therefore significantly improve the drug-like properties of compound 1. In addition, compound 1 is a rather flat molecule with a fraction of saturated carbons (Fsp 3 ) of 0.24. Fsp 3 is a newer index representing drug-likeness. 24 Lovering et al. pointed out that a decrease of Fsp 3 value would result in an increased incidence of CYP inhibition. 25 The desired Fsp 3 value is over 0.47 according to the literature. 24 Thus, we considered that improvement of the poor Fsp 3 value of compound 1 would be a rational way to overcome the CYP inhibi...

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

“…Overall ternary complex of mutant RORc-LBD bound with compound A Compound A derived from an initial hit compound is an orally efficacious inhibitor, which dose-dependently suppresses IL-17 production in vivo ( Fig. 1) (Hirata et al 2015). The synthesized compound selected by a unique dual fluorescence resonance Genes to Cells (2017) 22, 535-551 energy transfer (FRET) assay system showed not only co-activator releasing activity but also corepressor recruiting activity (Table 1).…”

“…This structure was determined using the dm hRORc-LBD after unsuccessful crystallization trials using the wild-type hRORc-LBD in the absence or in the presence of three kinds of corepressor peptides (NCoR, SMRT15 and SMRT22). Compound A is a selective and orally efficacious RORc inhibitor, derived from an initial hit compound after HTS campaigns by the dual FRET system (Thacher et al 2013;Hirata et al 2015). The inhibitor releases co-activator peptide and conversely recruits corepressor peptide as shown in the results of the dual FRET assay system.…”

“…A detailed description of synthesis for the compound 3z (described as compound A in this study) is described elsewhere (Hirata et al 2015).…”

“…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).…”

N‐Arylsulfonyl Indolines as Retinoic Acid Receptor‐Related Orphan Receptor γ (RORγ) Agonists

“…Given that activation of RORgtc ontrolsg ene programst hat enhancei mmunity,i ncrease IL17 production, and decrease immune suppression, [18,19] this NR has become ah igh-priority targetf or numerous pharmaceutical companies over the past decade. [20][21][22][23][24][25] Significant efforts to developsmall molecules that exhibit selectivei nverse agonist(repressive) activity against RORg for the treatment of autoimmune diseases has ultimately resulted in severalc linicalc andidates. [26,27] Ap lethora of diverse chemical scaffolds have been published that bind to the RORg oxysterol orthosteric site such as SR2211, [28] indole 1, [21] triazole 2, [22] and biaryl amide 3 [23] (Figure 1).…”