Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists

Yang, Ting; Liu, Qian; Cheng, Yaobang; Cai, Wei; Ma, Yingli; Yang, Liuqing; Wu, Qianqian; Orband‐Miller, Lisa A.; Zhou, Ling; Xiang, Zhijun; Huxdorf, Melanie; Zhang, Wei; Zhang, Jing; Xiang, Jia‐Ning; Leung, Stewart; Yang, Qi; Zhong, Zhong; Elliott, John D.; Lin, Xichen; Wang, Yonghui

doi:10.1021/ml4003875

Cited by 62 publications

(74 citation statements)

References 20 publications

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“…31 We previously showed that increasing size of a substituent on the phenyl ring of a tertiary amine RORt agonist could convert the agonist to an inverse agonist. 30 In this paper, it is the first time we observed that increasing size of a substituent on the phenyl ring of a thiazole ether RORt inverse agonist could convert the inverse agonist to an agonist.…”

Section: Resultsmentioning

confidence: 87%

“…27,28 RORt potency (pXC 50 ) and maximum response (%max) were measured in both FRET and dual FRET assays. 29,30 While the FRET assay is useful to identify antagonists, the dual FRET assay in which a surrogate agonist is not added allows the detection of both agonists and inverse agonists based on the changes in the basal level of RORt activity. 30 As we observed before, 27 addition of small alkyl groups such as Me (2a) and Et (2b) at 5-position of the thiazole ring did not change much of RORt activity in both FRET and dual FRET assays.…”

Section: Resultsmentioning

confidence: 99%

“…29,30 While the FRET assay is useful to identify antagonists, the dual FRET assay in which a surrogate agonist is not added allows the detection of both agonists and inverse agonists based on the changes in the basal level of RORt activity. 30 As we observed before, 27 addition of small alkyl groups such as Me (2a) and Et (2b) at 5-position of the thiazole ring did not change much of RORt activity in both FRET and dual FRET assays. However, replacing the small alkyl moiety with a bulky phenyl group (2c) increased RORt potency and decreased much of maximum percentage of inhibition in FRET assay.…”

Section: Resultsmentioning

confidence: 99%

“…28 The overall binding motif of 2c in RORt LBD is similar to a previously reported RORt agonist. 30 Two H-bonding interactions were formed: one between the ligand sulfone moiety with Arg367 as well as the backbone NH of Leu287, and the other between the ligand linker amide NH and a backbone carbonyl of Phe377. Two ligand phenyl rings are in π-π stacking with Phe377 and Phe388, respectively.…”

Section: Resultsmentioning

confidence: 99%

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

Wang

Yang

Liu

et al. 2015

Bioorganic & Medicinal Chemistry

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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

Wang

Yang

Liu

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Nonsubstituted biphenyl amide 8a showed a RORγ Predicted binding mode of compound 4i (brown) and structural overlay with a previously published tertiary amine (blue) cocrystal structure with RORγt LBD using Surflex-Dock v2.3 in Sybyl 8.1. 37 FRET pIC 50 of 6.3. Adding a Cl group on ortho-position of the central phenyl ring (8b) enhanced RORγt activity.…”

mentioning

confidence: 99%

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

Wang

Cai

Cheng

et al. 2015

ACS Med. Chem. Lett.

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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

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Immuno‐Oncology

Buesking

Mayes

Combs

2021

Burger's Medicinal Chemistry and Drug Discovery

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The ability to avoid immune surveillance and destruction is one of the hallmarks of cancer. Identification of ligands that can prevent immune cells from killing malignant cells was the pivotal discovery for which the 2018 Nobel Prize in Medicine was awarded and initiated the current era in cancer immunotherapy. As a result, a number of antibody‐based approaches including checkpoint inhibitors and bispecific antibodies have been explored. More recently, small molecule drugs have emerged as a complementary approach. Small molecules can offer unique advantages over antibody therapies including access to intracellular targets, opportunities for oral dosing, higher relative exposures in the brain, and increased penetration into tumors. This article provides a brief overview of antibody approaches and then summarizes nine immuno‐oncology targets for which small molecule modulators have been described in the peer‐review literature.

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Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists

Cited by 62 publications

References 20 publications

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

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

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

Immuno‐Oncology

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