New aminopropandiol derivatives as orally available and short-acting calcium-sensing receptor antagonists

Shinagawa, Yuko; Inoue, Teruhiko; Hirata, Keisuke; Katsushima, Takeo; Nakagawa, Takashi; Matsuo, Yoshitaka; Shindo, Masanori; Hashimoto, Harukichi

doi:10.1016/j.bmcl.2010.04.035

Cited by 8 publications

(8 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whereas anti-β-adrenergic activity of NPS-2143 and other biaryloxypropanol calcilytics is recognized (notably for the S-enantiomers) (Marquis et al, 2009; Widler, 2011), the interaction between the third generation beta antagonists and CaSR/GPRC6A has never been a subject of a scrutiny. However SAR studies suggest that transformations from NPS-2143 to S-bucindolol and S-carvedilol should generally retain calcilytic activity (Yang et al, 2005; Balan et al, 2009; Shinagawa et al, 2010; Kiefer et al, 2011; Shinagawa et al, 2011). Indeed, the reported IC50 for the CaSR of the Cpd9 variant of NPS-2143 (bucindolol) is 100 nm, not that different from NPS-2143 itself at 50 nm (Gavai et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

et al. 2019

View full text Add to dashboard Cite

Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Unexpectedly, both diastereomers 3a and 3b showed very poor oral bioavailability in rats (<10%) due to high plasma clearance [45]. Subsequently, it was discovered that oral future science group bioavailability could be strongly improved by replacing the phenoxy template with a benzyloxy moiety (FiguRe 3), an element first used by the Japan Tobacco group [42]. The diastereomeric mixture of 4 (IC 50 = 25 nM) was slightly less potent than 3, but one of its diastereomers had a bioavailability of more than 60%.…”

Section: Amino Alcoholsmentioning

confidence: 95%

“…The amino-alcohol lead structure discussed above also quickly attracted the interest of other pharmaceutical companies, first and foremost that of Japan Tobacco [42,[102][103][104]. Replacement of the phenyl ether of NPS 2143 by a 2-methylbenzyloxy group and the addition of a cyclopropyl substituent at the benzylic position afforded compound 1 (FiguRe 2), which was not only equipotent to NPS 2143 in vitro, but also induced a rapid and transient increase of endogenous plasma PTH at a dose of 10 mg/ kg in rats.…”

Section: Amino Alcoholsmentioning

confidence: 97%

Calcilytics: Antagonists of the Calcium-Sensing Receptor for the Treatment of Osteoporosis

Widler

2011

Future Med. Chem.

View full text Add to dashboard Cite

The only bone anabolic agents currently available on the market are based on the parathyroid hormone (PTH). Secretion of endogenous PTH is controlled by a calcium-sensing receptor at the surface of the parathyroid glands. Antagonists of this receptor (calcilytics) induce the release of the hormone. Provided the effect of the calcilytic is of short duration, a bone anabolic effect should also result. Although the first calcilytic series became known approximately 10 years ago, the number of different structural types is still small today. This article outlines the quest from hits to potent development candidates of all relevant calcilytic series currently known. Even after the front-runners unexpectedly failed in the clinic, the approach for an oral alternative to parenteral PTH remains highly attractive.

show abstract

“…Although many CaSR antagonists have been reported in the literature to date, − the proof of concept in humans was recently shown by ronacarelet and JTT-305 (MK-5442, 15 hemisulfate) (Figure ). We have reported a new aminopropandiol class of calcilytics 1 (Figure ) which demonstrated a rapid and transient stimulation of PTH secretion after oral administration in rats. , However, compound 1 possessed a strong CYP2D6 inhibition (IC 50 of 0.5 μM) and low bioavailability (BA, 13%).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Discovery of a Potent and Short−Acting Oral Calcilytic with a Pulsatile Secretion of Parathyroid Hormone

Shinagawa

Inoue

Katsushima

et al. 2010

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic drug used in the treatment of osteoporosis. Previously, we identified aminopropandiol 1, which transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cytochrome P450 (CYP) 2D6 and the low bioavailability of 1 remain to be solved. Attempts to change the physicochemical properties of the highly lipophilic amine 1 by introduction of a carboxylic acid group as well as further structural modifications led to the discovery of the highly potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a significantly improved bioavailability. Compound 15 evoked a rapid and transient elevation of endogenous PTH levels in rats after oral administration in a dose-dependent manner at a dose as low as 1 mg/kg. The PTH secretion pattern correlated with the pharmacokinetic profile and agreed well with that of the exogenous PTH injection which exerts a bone anabolic effect.

show abstract

New aminopropandiol derivatives as orally available and short-acting calcium-sensing receptor antagonists

Cited by 8 publications

References 12 publications

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine

Calcilytics: Antagonists of the Calcium-Sensing Receptor for the Treatment of Osteoporosis

Discovery of a Potent and Short−Acting Oral Calcilytic with a Pulsatile Secretion of Parathyroid Hormone

Contact Info

Product

Resources

About