Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency

Figures & data

Figure 1. Advanced GPR40 agonists containing the 3-[4-(benzyloxy)phenyl]propanoic acid core.

Figure 2. Design and retrosynthetic analysis of new series of FFA1 agonists 4.

Scheme 1. Synthesis of spirocyclic building blocks 2a–i from common precursor 3.

Scheme 2. Preparation of FFA1 agonists 4a–s studied in this work.

Table 1. Compounds 4a–i synthesized and FFA1 activation data obtained in this work.

Compound	R	Isolated yield, %	% FFA1 activation at 5 μM*	EC50 (μM)	% Efficacy*
4a		33	32.5	>20.0	n/a
4b		30	80.0	1.62	80
4c		30	61.4	0.90	61
4d		19	13.6	>20.0	n/a
4e		73	9.1	>20.0	n/a
4f		31	10.2	>20.0	n/a
4g		43	9.9	>20.0	n/a
4h		22	10.0	>20.0	n/a
4i		29	11.6	>20.0	n/a

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

Table 2. cLogP and EC₅₀ values for selected spirocyclic derivatives reported earlier (7 and 8) and investigated in this work (4b–c).

Compound	Structure	cLogP^14	FFA1 EC50 (μM)
7^12		4.69	>20.0
8^12		6.36	0.055
4b		4.03	1.82
4c		4.95	0.90

Calculated using Molinspiration Online Property Calculator. Available from: www.molinspiration.com [last accessed 20 July 2016].

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