Shaoyi Sun
Novartis
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Featured researches published by Shaoyi Sun.
Bioorganic & Medicinal Chemistry Letters | 2014
Shaoyi Sun; Qi Jia; Alla Yurevna Zenova; Mikhail Chafeev; Zaihui Zhang; Sophia Lin; Rainbow Kwan; Mike E. Grimwood; Sultan Chowdhury; Clint Young; Charles J. Cohen; Renata Oballa
The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.
Pharmaceutical patent analyst | 2014
Shaoyi Sun; Charles J Cohen; Christoph M Dehnhardt
There has been intense interest in developing inhibitors of the sodium channel Nav1.7 because genetic studies have established very strong validation for the efficacy to alleviate both inflammatory and neuropathic pain. This review summarizes patent applications targeting Nav1.7 since 2010 until May, 2014. We have classified the patents into three categories as follows: small molecules with well-defined molecular selectivity among sodium channel isoforms; biologicals with well-defined molecular selectivity; and, small molecules that inhibit Nav1.7 with unknown molecular selectivity. Most of the review is dedicated to small molecule selective compounds.
Journal of Medicinal Chemistry | 2013
Zaihui Zhang; Shaoyi Sun; Vishnumurthy Kodumuru; Duanjie Hou; Shifeng Liu; Nagasree Chakka; Serguei Sviridov; Sultan Chowdhury; David G. McLaren; Leslie G. Ratkay; Kuldip Khakh; Xing Cheng; Heinz W. Gschwend; Rajender Kamboj; Jianmin Fu; Michael D. Winther
Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC(50) = 14 nM and HepG2 IC(50) = 12 nM) and efficacious in vivo (ED(50) = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.
Medicinal Chemistry Research | 2013
Sultan Chowdhury; Shifeng Liu; Jay A. Cadieux; Tom Hsieh; Mikhail Chafeev; Shaoyi Sun; Qi Jia; Jianyu Sun; Mark Wood; Jonathan Langille; Serguei Sviridov; Jianmin Fu; Zaihui Zhang; Ray Chui; Audrey Wang; Xing Cheng; Jing Zhong; Sazzad Hossain; Kuldip Khakh; Ivana Rajlic; Henry Verschoof; Rainbow Kwan; Wendy B. Young
The structure–activity relationship of a new series of tetracyclic spirooxindoles led to the discovery of compound 25a, a potent hNaV1.7 blocker with improved ADME properties and in vivo efficacy in the CFA-induced inflammatory pain model.
Bioorganic & Medicinal Chemistry Letters | 2014
Shaoyi Sun; Zaihui Zhang; Vishnumurthy Kodumuru; Natalia Pokrovskaia; Julia Fonarev; Qi Jia; Po-Yee Leung; Jennifer Tran; Leslie G. Ratkay; David G. McLaren; Chris Radomski; Sultan Chowdhury; Jianmin Fu; Brian K. Hubbard; Michael D. Winther; Natalie Dales
Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg.
Bioorganic & Medicinal Chemistry | 2015
Shaoyi Sun; Zaihui Zhang; Natalia Pokrovskaia; Sultan Chowdhury; Qi Jia; Elaine Chang; Kuldip Khakh; Rainbow Kwan; David G. McLaren; Chris Radomski; Leslie G. Ratkay; Jianmin Fu; Natalie Dales; Michael D. Winther
Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings.
Bioorganic & Medicinal Chemistry Letters | 2014
Shaoyi Sun; Zaihui Zhang; Vandna Raina; Natalia Pokrovskaia; Duanjie Hou; Rostam Namdari; Kuldip Khakh; Leslie G. Ratkay; David G. McLaren; Monica Mork; Jianmin Fu; Suzie Ferreira; Brian K. Hubbard; Michael D. Winther; Natalie Dales
We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.
Journal of Medicinal Chemistry | 2018
Thilo Focken; Sultan Chowdhury; Alla Yurevna Zenova; Michael Edward Grimwood; Christine Chabot; Tao Sheng; Ivan William Hemeon; Shannon Decker; Michael T. Wilson; Paul Robert Bichler; Qi Jia; Shaoyi Sun; Clint Young; Sophia Lin; Samuel J. Goodchild; Noah Gregory Shuart; Elaine Chang; Zhiwei Xie; Bowen Li; Kuldip Khakh; Girish Bankar; Matthew Waldbrook; Rainbow Kwan; Karen Nelkenbrecher; Parisa Karimi Tari; Navjot Chahal; Luis E. Sojo; C. Lee Robinette; Andrew D. White; Chien-An Chen
The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.
Bioorganic & Medicinal Chemistry | 2013
Shaoyi Sun; Richard Dean; Qi Jia; Alla Yurevna Zenova; Jing Zhong; Celene Grayson; Clark Xie; Andrea Lindgren; Pritpaul Samra; Luis Sojo; Margaret van Heek; Linus S. Lin; David Percival; Jianmin Fu; Michael Winther; Zaihui Zhang
Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice.
Archive | 2004
Nagasree Chakka; Mikhail Chafeev; Sultan Chowdhury; Jianmin Fu; Duanjie Hou; Rajender Kamboj; Vishnumurthy Kodumuru; Shifeng Liu; Vandna Raina; Shaoyi Sun; Serguei Sviridov; Michael D. Winther; Zaihui Zhang; Melwyn Abreo; Mark W. Holladay; Wenbao Li; Sengen Sun; Chi Tu; Heinz W. Gschwend