GSK256073 acutely regulates NEFA levels via HCA2 agonism but does not achieve durable glycaemic control in type 2 diabetes. A randomised trial.

This study investigated safety and efficacy of GSK256073, an in vitro potent, selective GPR109A agonist, for treatment of subjects with type 2 diabetes mellitus (Type 2 DM) poorly controlled with metformin alone. Patients with Type 2 DM (n=94) were enroled into this randomised, double-blind (sponsor unblinded), placebo-controlled, parallel group trial. Participants received placebo for two weeks before being randomised (2:2:2:2:1:1) to receive doses of GSK256073 5mg twice-daily (BID), 10mg once-daily (QD), 25mg BID, 50mg QD or placebo BID or QD in addition to their current metformin treatment. The primary efficacy endpoint was change from baseline in glycosylated haemoglobin (HbA1c) at week 12. The safety profile of GSK256073 did not significantly differ from that of placebo. Decreases from baseline in HbA1c were observed in all treatment groups but were not statistically significant compared to placebo; at week 12 a maximum decrease of 0.30% from placebo was reached in the GSK256073 50mg QD group. On day 2, GSK256073 significantly decreased non-esterified fatty acid (NEFA) (0-12h) concentrations but pharmacological activity was lost (5mg BID, 10mg QD, 25mg BID) or reduced (50mg QD) at week 6. Drug exposure demonstrated 2-fold accumulation over 6 weeks. The primary efficacy objective of the study was not met. GSK256073 did not improve HbA1c concentrations at week 12. Despite sustained drug exposure, the ability of the HCA2 agonist to suppress plasma NEFA concentrations waned over time and targeted effects on glucose oxidation and insulin sensitivity subsided.

The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues.

Starting from ethyl beta-carboline-3-carboxylate (beta-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-beta-carboline derivatives has been identified as a novel chemical class of potent and selective PDE5 inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compound 2 and of the aromatic ring on position 5 led to the identification of compound 6e, a highly potent and selective PDE5 inhibitor, with greater selectivity for PDE5 vs PDE1-4 than sildenafil. Compound 6e demonstrated a long-lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.

The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues.

Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).