Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor

Abstract

A novel orally bioavailable renin inhibitor, , showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC 50 = 0.9 nM) and human and monkey PRA (IC 50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.

An Efficient Synthesis of (3S,5S)-5-[3,3-Dimethyl-1-(o-tolyl)-6-oxo-2H-pyridin-4-yl]piperidine-3-carboxamide as Potent Renin Inhibitor

“…Ozonolysis of the terminal vinyl group of 6 delivered aldehyde 13 in 81% yield. Especially, inhibitory activity against purified human renin (0.7 nM) was higher than that of 1 (1.5 nM, in-house data) 9 or 3 (1.6 nM). The aniline 14 was acylated with freshly prepared CH 2 Cl 2 solution of phosphorylacetyl chloride 15, 15 providing the phosphono acetanilide 16 in 88% yield.…”

“…3a,b It has long been hypothesized that inhibition of renin, which is the rate-limiting enzyme in the RAAS cascade, may represent the most attractive therapeutic strategy to block the RAAS. 5,6 In the preceding papers, 7,8 starting from our clinical candidate DS-8108b (2), 9,10 we discovered a 3,5-disubstituted piperidine derivative with 2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl group at the 5-position as a new type of renin inhibitor (Figure 1). 5,6 In the preceding papers, 7,8 starting from our clinical candidate DS-8108b (2), 9,10 we discovered a 3,5-disubstituted piperidine derivative with 2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl group at the 5-position as a new type of renin inhibitor (Figure 1).…”

“…The potent compound 3 obtained by the chemical modification of the P 1 ', P 2 ' and P 3 portion showed a significant BP lowering effect by oral administration in two hypertensive animal models, double transgenic rats 11 and furosemide pretreated cynomolgus monkeys. 9,12 However, the interaction between basic nitrogen on 5,5-dimethylpiperazin-2-one ring and the target enzyme was not observed. Regarding the P 1 portion, we previously reported the existence of hydrophobic interaction of gem-dimethyl group on 5,5-dimethylpiperazin-2-one ring with S 1 pocket of human renin as well as hydrogen bond interaction between the carboxamide oxygen on the ring and Tyr77 by X-ray crystallography.…”

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

“…Although it had low cardiac toxicity and suppressed PRA in the cynomolgus monkey more effectively than that of aliskiren, it proved to be clinically inefficient. 49…”

“…Thus, patients are advised to take aliskiren in a similar way every day adhering to meal times. 48,49 Aliskiren has a lower potential for considerable drug interaction. Remarkably, only 20% of aliskiren is metabolized in humans.…”