The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470)

The
G protein-coupled receptor 40 (GPR40) also known as free fatty
acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells
and responds to endogenous fatty acids, resulting in amplification
of insulin secretion only in the presence of elevated glucose levels.
Hypothesis driven structural modifications to endogenous FFAs, focused
on breaking planarity and reducing lipophilicity, led to the identification
of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40
agonists with unique pharmacology, selectivity, and pharmacokinetic
properties. Compounds 1 (LY2881835), 2 (LY2922083),
and 3 (LY2922470) demonstrated potent, efficacious, and
durable dose-dependent reductions in glucose levels along with significant
increases in insulin and GLP-1 secretion during preclinical testing.
A clinical study with 3 administered to subjects with
T2DM provided proof of concept of 3 as a potential glucose-lowering
therapy. This manuscript summarizes the scientific rationale, medicinal
chemistry, preclinical, and early development data of this new class
of GPR40 agonists.