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. 2015 Nov 20;7(1):51-5.
doi: 10.1021/acsmedchemlett.5b00323. eCollection 2016 Jan 14.

Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

Sameer Agarwal  1 , Amit Patil  1 , Umesh Aware  1 , Prashant Deshmukh  1 , Brijesh Darji  1 , Santosh Sasane  1 , Kalapatapu V V M Sairam  1 , Priyanka Priyadarsiny  1 , Poonam Giri  1 , Harilal Patel  1 , Suresh Giri  1 , Mukul Jain  1 , Ranjit C Desai  1
Affiliations

Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

Sameer Agarwal et al. ACS Med Chem Lett. .

Abstract

TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg.

Keywords: GLP1 secretion; GPBAR1; GPR 131; TGR5; TGR5 agonist; diabetes.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Selected bile acid and nonbile acid TGR5 receptor agonist reported in literature. (b) Schematic representation of ligand optimization.
Scheme 1
Scheme 1. Synthesis of Compound 6
Reagent and conditions: (a) MeI, NaH, THF, 0 °C to r.t., 3 h, 93%; (b) DIBAL, toluene, −78 °C, 2 h, 93%; (c) MeMgBr, dry Et2O, 0 °C to r.t., 80%; (d) oxalyl chloride, DMSO, Et3N, DCM, −78 °C, 2 h, 82%; (e) Bu4NBr3, DCM, MeOH, 0 °C to r.t., 7 h, 100%; (f) HMTA, DCM, r.t., 48 h; (g) EtOH, HCl, 80 °C, 3 h; (h) 1-fluoro-4-isothiocyanatobenzene, Et3N, DCM, 0 °C to r.t., 1 h, 42%; (i) AcOH, 118 °C, 3 h, 73%; (j) 1,2-dibromoethane, K2CO3, acetone, r.t., 2 h, 73%; (k) substituted phenol, K2CO3, DMF, 90 °C, 3–5 h.
Figure 2
Figure 2
Binding mode of 6g in homology model of TGR5 receptor.
Figure 3
Figure 3
(a) In vivo GLP-1 secretion study of 6g in C57 (n = 4 animals/group; female C57 mice; po 30 mg/kg; formulation, 5% Tween 20 + 0.5% sodium CMC (95%); ***P < 0.001 versus control; error bar indicates SEM). (b) In vivo efficacy of 6g in DIO C57 mice (n = 4 animals/group; formulation, 5% Tween 20 + 0.5% sodium CMC (95%); *P < 0.05; **P < 0.005 versus control; error bar indicates SEM).
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