Novel agonists of free fatty acid receptor 1 (GPR40) based on 3-(1,3,4-thiadiazol-2-yl)propanoic acid scaffold

Figures & data

Figure 1. Structures of TAK-875 and of the heterocyclic analogs of 3-phenylpropanoic acid-based GPR40 agonists 1–4.

Figure 2. Design of new 1,3,4-thiadiazole-containing inhibitors explored in this work.

Scheme 1. Synthesis of 3-(1,3,4-thiadiazol-2-yl)propanoic acids 8a--m studied in this work.

Table 1. Compounds 7(8)a--m synthesized in this work and GPR40 activation data obtained for 8a--m.

Compound	Ar	Yield of 7, %	Yield of 8, %	% GPR40 activation at 5 μM*
7(8)a		55	73	33.2
7(8)b		71	87	28.6
7(8)c		55	80	13.2
7(8)d		64	76	52.7
7(8)e		77	91	31.4
7(8)f		70	81	36.7
7(8)g		59	84	59.9
7(8)h		62	95	38.3
7(8)i		73	91	18.6
7(8)j		45	65	57.0
7(8)k		54	78	32.8
7(8)l		76	90	63.9
7(8)m		40	72	32.3

*Relative to GPR40 activation by 20 μM of GW9509, n  =  2.

Table 2. EC₅₀ values for compounds 8d, 8 g, 8j and 8 l.

Compound	Structure	EC50 ±SD, μM*
8d		3.32 ± 0.54
8g		5.93 ± 0.23
8j		24.2 ± 2.34
8l		9.85 ± 0.56

*Each value is an average of n  =  4.

Figure 3. Dose-response curves for compounds 8d, 8 g, 8j and 8l used to determine EC₅₀ values.

Table 3. Further in vitro characterization of lead compound 8g.

Plasma protein binding (human)*	89.9%
Aqueous solubility (PBS, pH 7.4)^†	>800 μM
Microsomal stability (mouse, t1/2)^‡	1324 min

*Each value is an average of n  =  4, measured at c  =  1 μM.

† Each value is an average of n  =  2.

‡ Each value is an average of n  =  5, measured at c  =  2 μM.