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SAR Exploration Guided by LE and Fsp: Discovery of a Selective and Orally Efficacious ROR# Inhibitor Kazuyuki Hirata, Masayuki Kotoku, Noriyoshi Seki, Takaki Maeba, Katsuya Maeda, Shintaro Hirashima, Takayuki Sakai, Shingo Obika, Akimi Hori, Yasunori Hase, Takayuki Yamaguchi, Yoshiaki Katsuda, Takahiro Hata, Naoki Miyagawa, Arita Kojo, Yukihiro Nomura, Kota Asahina, Yusuke Aratsu, Masafumi Kamada, Tsuyoshi Adachi, Masato Noguchi, Satoki Doi, Paul Crowe, Erin Bradley, Ruo Steensma, Haiyan Tao, Morgan Fenn, Robert Babine, Xiaolin Li, Scott Thacher, Hiromasa Hashimoto, and Makoto Shiozaki ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00253 • Publication Date (Web): 04 Nov 2015 Downloaded from http://pubs.acs.org on November 9, 2015
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Laboratories Noguchi, Masato; JAPAN TOBACCO INC., Pharmaceutical Frontier Research Laboratories Doi, Satoki; JAPAN TOBACCO INC., Pharmaceutical Frontier Research Laboratories Crowe, Paul; Orphagen Pharmaceuticals, Bradley, Erin; Corvus Pharmaceuticals Inc., Steensma, Ruo; Janssen Research & Development, Tao, Haiyan; Orphagen Pharmaceuticals, Fenn, Morgan; Orphagen Pharmaceuticals, Babine, Robert; Rebexsess Discovery Chemistry, Li, Xiaolin; GIMDx Inc., Thacher, Scott; Orphagen Pharmaceuticals, Hashimoto, Hiromasa; JAPAN TOBACCO INC., Central Pharmaceutical Research Institute Shiozaki, Makoto; JAPAN TOBACCO INC., Central Pharmaceutical Research Institute
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SAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγγ Inhibitor Kazuyuki Hirata,† Masayuki Kotoku,† Noriyoshi Seki,† Takaki Maeba,† Katsuya Maeda,† Shintaro Hirashima,† Takayuki Sakai,† Shingo Obika,† Akimi Hori,† Yasunori Hase,† Takayuki Yamaguchi,§ Yoshiaki Katsuda,§ Takahiro Hata,§ Naoki Miyagawa,§ Kojo Arita,§ Yukihiro Nomura,¶ Kota Asahina,¶ Yusuke Aratsu,¶ Masafumi Kamada,# Tsuyoshi Adachi,# Masato Noguchi,# Satoki Doi,# Paul Crowe,‡ Erin Bradley‡,∆ Ruo Steensma,‡,∞ Haiyan Tao,‡ Morgan Fenn,‡ Robert Babine,‡,£ Xiaolin Li,‡,¢ Scott Thacher,‡ Hiromasa Hashimoto† and Makoto Shiozaki*,† †
Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, ¶Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki Osaka, 569-1125, Japan, #Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-ku, Yokohama Kanagawa, 236-0004, Japan, ‡Orphagen Pharmaceuticals, 11558 Sorrento Valley Road, Suite 4, San Diego, California, 92121, United States KEYWORDS. Th17, immunological diseases, nuclear receptor, RORγ, ligand efficiency (LE), fraction of sp3 carbon atoms (Fsp3)
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 sp3 carbon atoms (Fsp3), 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.
Two 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 EC50 = 1.7 µM, FRET EC50 = 0.85 µM), compound 1 also demonstrated >20 fold selectivity over 5 nuclear receptors (hRORα, hFXR, hRXRα, hPR, 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 (IC50 = 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 Kuntz22 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 (Fsp3) of 0.24. Fsp3 is a newer index representing druglikeness.24 Lovering et al. pointed out that a decrease of Fsp3 value would result in an increased incidence of CYP inhibition.25 The desired Fsp3 value is over 0.47 according to the literature.24 Thus, we considered that improvement of the poor Fsp3 value of compound 1 would be a rational way to overcome the CYP inhibition liability. As a result of the above
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analysis, we decided to optimize compound 1 by improving two drug-likeness metrics, LE and Fsp3, aiming to improve metabolic stability and reduce CYP inhibition.
hydrogen bonds to both Arg364 (2.91 Å) and Glu379 (2.95 Å). The structure also suggested that the van der Waals contacts of the cyclohexylethyl moiety was important and fine tuning of this part was attempted later during the final optimization.
Table 1. Initial SAR Exploration N N
Ile397
O
1
R
2
N
X
N H
R
Trp317
Me
Compd
1
R
X
2
R
RORγ-LUC EC50 (µ M) human mouse
Phe377 LEa
3b
Fsp
SCH2
1.7
2
OCH2
>20
>20 20
>20 20
4.5
