Original Research| Volume 44, ISSUE 2, P269-281, February 2022

Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of SY-004, a Glucokinase Activator, in Healthy Chinese Adults: A Randomized, Phase Ia, Single-Ascending Dose Study



      SY-004, a dual-acting full glucokinase activator, is under development to provide a dose-dependent improvement of glucose control. This study aimed to assess the tolerability, safety, and pharmacokinetic and pharmacodynamic properties of SY-004 in healthy Chinese adults.


      Two study participants were administered 2 mg of SY-004 in the 2-mg cohort, whereas 6 study participants were randomized with 4 study participants receiving SY-004 and 2 receiving placebo in the 20-mg cohort. In each of other 3 dose cohorts (40, 80, and 120 mg), 12 participants were randomized in a 10:2 ratio to receive single oral SY-004 capsules or placebos. Drug concentrations, glucose and insulin levels, and safety data were assessed and analyzed. Noncompartmental analysis was used to determine SY-004 pharmacokinetic parameters.


      SY-004 was generally well tolerated. Nine of the 44 study participants reported 17 treatment-related adverse events, and most treatment-related adverse events were mild. SY-004 had approximately dose-proportional increases in systemic exposure. The mean t½ ranged from 37.6 to 49.9 hours, and CL/F values ranged from 67.1 to 110 L/h across all doses. The cumulative amounts of the unchanged drug excreted in urine were very low, accounting for no more than 1.53% of the given doses. No significant difference in sex was observed in pharmacokinetic parameters. The pharmacodynamic response appeared to slightly correlate with dose.


      SY-004, a new potential glucokinase activator, had favorable safety profiles and good PK characteristics. The glucose-lowering effects were slightly dose related. The SY-004 data in healthy Chinese adults supports further development. identifier: NCT03171623.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • IDF
        IDF Diabetes Atlas.
        9th edition. International Diabetes Federation, 2019 (
        • Naito R
        • Miyauchi K.
        Coronary Artery Disease and Type 2 Diabetes Mellitus.
        Int Heart J. 2017; 58: 475-480
        • Braunwald E.
        Diabetes, heart failure, and renal dysfunction: the vicious circles.
        Prog Cardiovasc Dis. 2019; 62: 298-302
        • Stino AM
        • Rumora AE
        • Kim B
        • Feldman EL.
        Evolving concepts on the role of dyslipidemia, bioenergetics, and inflammation in the pathogenesis and treatment of diabetic peripheral neuropathy.
        J Peripher Nerv Syst. 2020; 25: 76-84
        • Sagoo MK
        • Gnudi L.
        Diabetic nephropathy: an overview.
        Methods Mol Biol. 2020; 2067: 3-7
        • Jayaraj RL
        • Azimullah S
        • Beiram R.
        Diabetes as a risk factor for Alzheimer's disease in the Middle East and its shared pathological mediators.
        Saudi J Biol Sci. 2020; 27: 736-750
        • Inaishi J
        • Saisho Y.
        Beta-cell mass in obesity and type 2 diabetes, and its relation to pancreas fat: a mini-review.
        Nutrients. 2020; 12: 3846
        • Keresztes P
        • Peacock-Johnson A.CE
        Type 2 diabetes: a pharmacologic update.
        Am J Nurs. 2019; 119: 32-40
        • Scheen AJ.
        New hope for glucokinase activators in type 2 diabetes?.
        Lancet Diabetes Endocrinol. 2018; 6: 591-593
        • Nakamura A
        • Terauchi Y.
        Present status of clinical deployment of glucokinase activators.
        J Diabetes Investig. 2015; 6: 124-132
        • Fonseca VA.
        Defining and characterizing the progression of type 2 diabetes.
        Diabetes Care. 2009; 32: S151-S156
        • Tahrani AA
        • Bailey CJ
        • Del Prato S
        • Barnett AH.
        Management of type 2 diabetes: new and future developments in treatment.
        Lancet. 2011; 378: 182-197
        • Zhu D
        • Gan S
        • Liu Y
        • et al.
        Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled, phase 2 study.
        Lancet Diabetes Endocrinol. 2018; 6: 627-636
        • Chakraborti CK.
        Exenatide: a new promising antidiabetic agent.
        Indian J Pharm Sci. 2010; 72: 1-11
        • Toulis KA
        • Nirantharakumar K
        • Pourzitaki C
        • Barnett AH
        • Tahrani AA.
        Glucokinase activators for type 2 diabetes: challenges and future developments.
        Drugs. 2020; 80: 467-475
        • Osbak KK
        • Colclough K
        • Saint-Martin C
        • et al.
        Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.
        Hum Mutat. 2009; 30: 1512-1526
        • Haeusler RA
        • Camastra S
        • Astiarraga B
        • Nannipieri M
        • Anselmino M
        • Ferrannini E.
        Decreased expression of hepatic glucokinase in type 2 diabetes.
        Mol Metab. 2015; 4: 222-226
        • Grewal AS
        • Sekhon BS
        • Lather V.
        Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus.
        Mini Rev Med Chem. 2014; 14: 585-602
        • Guertin KR
        • Grimsby J.
        Small molecule glucokinase activators as glucose lowering agents: a new paradigm for diabetes therapy.
        Curr Med Chem. 2006; 13: 1839-1843
        • Matschinsky FM
        • Porte D.
        Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics.
        F1000 Med Rep. 2010; 2: 43
        • Matschinsky FM
        • Zelent B
        • Doliba NM
        • et al.
        Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects.
        Handb Exp Pharmacol. 2011; : 357-401
        • Zheng S
        • Shao F
        • Ding Y
        • et al.
        Safety, pharmacokinetics, and pharmacodynamics of globalagliatin, a glucokinase activator, in Chinese patients with type 2 diabetes mellitus: a randomized, phase Ib, 28-day ascending dose study.
        Clin Drug Investig. 2020; 40: 1155-1166
        • Smith BP
        • Vandenhende FR
        • DeSante KA
        • et al.
        Confidence interval criteria for assessment of dose proportionality.
        Pharm Res. 2000; 17: 1278-1283
        • Naderer OJ
        • Dumont E
        • Zhu J
        • Kurtinecz M
        • Jones LS.
        Single-dose safety, tolerability, and pharmacokinetics of the antibiotic GSK1322322, a novel peptide deformylase inhibitor.
        Antimicrob Agents Chemother. 2013; 57: 2005-2009
        • Liang H
        • Guan W
        • Yang Y
        • et al.
        Roux-en-Y gastric bypass for Chinese type 2 diabetes mellitus patients with a BMI < 28 kg/m(2): a multi-institutional study.
        J Biomed Res. 2015; 29: 112-117
        • Tahrani AA
        • Barnett AH
        • Bailey CJ.
        Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus.
        Nat Rev Endocrinol. 2016; 12: 566-592
        • Vella A
        • Freeman JLR
        • Dunn I
        • Keller K
        • Buse JB
        • Valcarce C.
        Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator.
        Sci Transl Med. 2019; 11: eaau3441
        • Pettersen JC
        • Litchfield J
        • Neef N
        • et al.
        The relationship of glucokinase activator-induced hypoglycemia with arteriopathy, neuronal necrosis, and peripheral neuropathy in nonclinical studies.
        Toxicol Pathol. 2014; 42: 696-708
        • Matschinsky FM.
        GKAs for diabetes therapy: why no clinically useful drug after two decades of trying?.
        Trends Pharmacol Sci. 2013; 34: 90-99
        • Li W
        • Zhang X
        • Sun Y
        • Liu Z.
        Recent clinical advances of glucokinase activators in the treatment of diabetes mellitus type 2.
        Pharmazie. 2020; 75: 230-235
        • Fujieda H
        • Kogami M
        • Sakairi M
        • et al.
        Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus.
        Eur J Med Chem. 2018; 156: 269-294
        • Ericsson H
        • Roshammar D
        • Wollbratt M
        • et al.
        Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp.
        Int J Clin Pharmacol Ther. 2012; 50: 765-777
        • Bonadonna RC
        • Heise T
        • Arbet-Engels C
        • et al.
        Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study.
        J Clin Endocrinol Metab. 2010; 95: 5028-5036
        • Xu H
        • Sheng L
        • Chen W
        • et al.
        Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study.
        Drug Des Devel Ther. 2016; 10: 1619-1626