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Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.

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Alkyl-substituted benzothiadiazides (BTDs) were tested for their effects on (R,S)-␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. In excised patches, the 5Ј-ethyl derivative "D1" blocked the desensitization of AMPA receptor currents during prolonged application of glutamate (EC 50 , 36 M), and it slowed deactivation of responses elicited by 1-ms glutamate pulses greater than 10-fold. [3 H]Fluorowillardiine binding to rat synaptic membranes was increased by D1 by a factor of 3.6 (EC 50 , 17 M) with a Hill coefficient near 2. In hippocampal slices, the compound reversibly increased excitatory postsynaptic currents and field excitatory postsynaptic potentials (EPSPs) with thresholds around 10 M. The size of the alkyl substituent influenced both the potency and nature of the drug effect on synaptic currents: 5Ј-methyl compounds had a 2-fold greater effect on response amplitude than on response duration, whereas 5Ј-ethyl compounds like D1 caused greater increases in duration than amplitude. In tests with recombinantly expressed AMPA receptor subunits, D1 preferred the glutamate receptor (GluR) subunit GluR4 flip (0.64 M) over GluR4 flop (5.3 M); similar affinities but with smaller flip-flop differences were obtained for GluR1 through 3. These results show that D1 and congeners are significantly more potent than the parent compound IDRA-21 and that they differ in two fundamental aspects from cyclothiazide, the most widely studied BTD: 1) D1 markedly increases the agonist affinity of AMPA receptors and 2) it has immediate and large effects on field EPSPs. The large gain in potency conferred by alkyl substitution suggests that the 5Ј substituent is in intimate contact with the receptor, with the size of the substituent determining the way in which receptor kinetics is changed.