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...

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)­butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure−activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.