Discovery of phenyl acetamides as potent and selective GPR119 agonists

doi:10.1016/j.bmcl.2017.01.091

Bioorganic & Medicinal Chemistry Letters

Volume 27, Issue 5, 1 March 2017, Pages 1124-1128

https://doi.org/10.1016/j.bmcl.2017.01.091 Get rights and content

Abstract

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.

Graphical abstract

Section snippets

Acknowledgments

We would like to thank Dr. Greg Morriello, Mr. Lehua Chang, Mr. Chris Moyes and Mr. Nam Fung Kar for intermediate 3 syntheses. Cheng Zhu would like to thank Dr. Milana Maletic, Mr. Kake Zhao and Mrs. Wanying Sun for helpful discussions.

References (20)

Z.L. Chu et al.
Endocrinology
(2007)
E.H. Kerns et al.
Drug Discovery Today
(2003)
N.A. Meanwell
Chem Res Toxicol
(2011)
J.S. Scott et al.
J Med Chem
(2012)
V. Chu
Drug Metab Dispos
(2009)
Center for Disease Control and Prevention, Diabetes Public Health Resource; 2015....
R.M. Jones et al.
Expert Opin Ther Pat
(2009)
H.S. Hansen et al.
Trends Pharmacol Sci
(2012)
T. Ohishi et al.
Expert Opin Invest Drugs
(2012)
J.W. Polli et al.
Xenobiotica
(2013)
L.B. Katz et al.
Diabetes Obes Metab
(2012)
K. Ritter et al.
J Med Chem
(2016)
P. Liu et al.
ACS Med Chem Lett
(2015)

There are more references available in the full text version of this article.

Cited by (9)

GPR119 agonists: Novel therapeutic agents for type 2 diabetes mellitus
2021, Bioorganic Chemistry
Citation Excerpt :
Overall, research analysis formed outcomes that are reliable with the conclusions that compound “25” is significant for targeting GPR119 agonist activity for the treatment of T2DM with hypoglycaemic effect with their chemical properties and primary pharmacology activity. Zhu et al. [121] discovered GPR119 agonist agents containing derivatives of phenyl acetamide for the management of T2DM. The phenoxy containing compound was chosen as the lead compound, while the modification in the phenoxy group to the corresponding benzyloxy moiety was found to result in a desirable decrease in hydrophobicity and decreased boundless distribution.
Diabetes mellitus type 2 (T2D) is a group of genetically heterogeneous metabolic disorders whose frequency has gradually risen worldwide. Diabetes mellitus Type 2 (T2D) has started to achieve a pandemic level, and it is estimated that within the next decade, cases of diabetes might get double due to increase in aging population. Diabetes is rightly called the 'silent killer' because it has emerged to be one of the major causes, leading to renal failure, loss of vision; besides cardiac arrest in India. Thus, a clinical requirement for the oral drug molecules monitoring glucose homeostasis appears to be unmet. GPR119 agonist, a family of G-protein coupled receptors, usually noticed in β-cells of pancreatic as well as intestinal L cells, drew considerable interest for type 2 diabetes mellitus (T2D). GPR119 monitors physiological mechanisms that enhance homeostasis of glucose, such as glucose-like peptide-1, gastrointestinal incretin hormone levels, pancreatic beta cell-dependent insulin secretion and glucose-dependent insulinotropic peptide (GIP). In this manuscript, we have reviewed the work done in the last five years (2015–2020) which gives an approach to design, synthesize, evaluate and study the structural activity relationship of novel GPR119 agonist-based lead compounds. Our article would help the researchers and guide their endeavours in the direction of strategy and development of innovative, effective GPR119 agonist-based compounds for the management of diabetes mellitus type 2.
Discovery of a potent G-protein-coupled receptor 119 agonist for the treatment of type 2 diabetes
2021, Bioorganic and Medicinal Chemistry
Citation Excerpt :
The activation of GPR119 receptor expressed in enteroendocrine cells of intestine is shown to modulate incretin hormone release, a key function in maintaining glucose homeostasis. Thus the effects of GPR119 activation on glucose homeostasis are two fold, a direct action of glucose stimulated insulin secretion in pancreatic β-cell and an indirect action of stimulating the release of GLP-1 and GIP in enteroendocrine cells of intestine.16–20 This glucose-dependent dual mechanism of action makes GPR119 a promising target for discovery of anti-diabetic agents with low risk of hypoglycemia and body weight gain.
The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.
Synthesis and evaluation of novel fused pyrimidine derivatives as GPR119 agonists
2019, Bioorganic Chemistry
Citation Excerpt :
GPR119 is a class A type of G Protein coupled receptor, which is expressed primarily in pancreatic β-cells and the K and L cells of the gastrointestinal tract [1–3]. Activation of GPR119 promotes secretion of incretins such as glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose dependent release of insulin in pancreatic β-cells [4–8]. The dual mechanism makes GPR119 a promising target for discovery of anti-diabetic agents with low risk of hypoglycemia.
A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC₅₀ values (0.27–1.2 μM) though they appeared to be partial agonists.
Four-Membered Ring Systems
2018, Progress in Heterocyclic Chemistry
Citation Excerpt :
2-Fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoyl carbamate 6 has potent human vascular adhesion protein-1 (VAP-1) inhibitory activity and excellent aqueous solubility without CYP inhibition and has shown favorable oral bioavailability in rats, dogs, and monkeys (17BMC6024). A paper describes the structure–activity relationship/structure–property relationship (SAR/SPR) studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivative 7 as a potent and selective G protein–coupled receptor 119 agonist (17BMCL1124). Image
Novel targets for potential therapeutic use in Diabetes mellitus
2023, Diabetology and Metabolic Syndrome
An Efficient Palladium-Catalysed Aminocarbonylation of Benzyl Chlorides
2020, Synlett

View all citing articles on Scopus

View full text

Discovery of phenyl acetamides as potent and selective GPR119 agonists

Abstract

Graphical abstract

Section snippets

Acknowledgments

Endocrinology

Drug Discovery Today

Chem Res Toxicol

J Med Chem

Drug Metab Dispos

Expert Opin Ther Pat

Trends Pharmacol Sci

Expert Opin Invest Drugs

Xenobiotica

Diabetes Obes Metab

J Med Chem

ACS Med Chem Lett