Discovery of a series of 2-(pyridinyl)pyrimidines as potent antagonists of GPR40

Abstract

A series of 2-(pyridinyl)pyrimidines were identified as potent GPR40 antagonists.

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

“…Further chemical modification identified the optimal FFAR1 antagonist 139 (IC 50 = 158 nM), which provided reasonable PK properties in rats (CL = 30 mL/min/kg, V ss = 3.0 L/kg, F = 32%) despite poor solubility (1.2 μg/mL) and some hERG activity (pIC 50 = 5.0). During the β 3 ‐agonist challenge in insulin resistant Zucker fa/fa rats, antagonist 139 revealed a decrease in insulin levels from 35 ng/mL to 18 ng/mL, suggesting a complete inhibition of the nonesterified fatty acids mediated GSIS …”

“…However, ANT203 suffered from low solubility (< 0.086 μg/mL) and poor bioavailability, probably due to the nondrug‐like hydrazone moiety and high lipophilicity (log D 7.4 = 4.3). To identify drug‐like FFAR1 antagonists, an AstraZeneca team carried out a high‐throughput screen of their compound collection using Ca 2+ flux as an alternative endpoint, which led to the discovery of a 2‐(pyridinyl)pyrimidine hit . Further chemical modification identified the optimal FFAR1 antagonist 139 (IC 50 = 158 nM), which provided reasonable PK properties in rats (CL = 30 mL/min/kg, V ss = 3.0 L/kg, F = 32%) despite poor solubility (1.2 μg/mL) and some hERG activity (pIC 50 = 5.0).…”

“…To identify drug-like FFAR1 antagonists, an AstraZeneca team carried out a high-throughput screen of their compound collection using Ca 2+ flux as an alternative endpoint, which led to the discovery of a 2-(pyridinyl)pyrimidine hit. 214 Further chemical modification identified the optimal FFAR1 antagonist 139 (IC 50 = 158 nM), which provided reasonable PK properties in rats (CL = 30 mL/min/kg, V ss = 3.0 L/kg, F = 32%) despite poor solubility (1.2 μg/mL) and some hERG activity (pIC 50 = 5.0). During the β 3 -agonist challenge in insulin resistant Zucker fa/fa rats, antagonist 139 revealed a decrease in insulin levels from 35 ng/mL to 18 ng/mL, suggesting a complete inhibition of the nonesterified fatty acids mediated GSIS.…”

“…During the β 3 -agonist challenge in insulin resistant Zucker fa/fa rats, antagonist 139 revealed a decrease in insulin levels from 35 ng/mL to 18 ng/mL, suggesting a complete inhibition of the nonesterified fatty acids mediated GSIS. 214 Using virtual screening based on an FFAR1 homology model, researchers at the Shanghai Institute of Materia Medica identified a new class of sulfonamide FFAR1 antagonists, such as DC260126, which dose dependently inhibited the FFAR1-mediated Ca 2+ influx promoted by linoleic acid, palmitoleic acid, oleic acid, and lauric acid, with IC 50 values of 6.28, 7.07, 5.96, and 4.58 μM, respectively. Moreover, DC260126 decreased the ERK1/2 phosphorylation and GTP-loading induced by linoleic acid, suppressed palmitic acid mediated GSIS, and negatively modulated oleic acid-induced FFAR1 mRNA expression.…”

Pot, Atom, Step Economic (PASE) Approach towards (Aza)‐2,2′‐Bipyridines: Synthesis and Photophysical Studies

“…( Aza )‐2,2′‐bipyridines, such as pyrazinyl and pyrimidinyl‐pyridines, like 4‐methoxybipyridines, are of special interest due to their biological activities. Particularly, pyrimidine derivatives have been reported as inhibitors of hypoxia‐inducible factor‐1 (HIF‐1α), inhibitors of human cellular proteins MetAP1 (HsMetAP1, responsible for cell proliferation) and human MetAP2 (HsMetAP2, responsible for anginogenesis), and also as antidiabetic drugs (Figure ) …”