Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists

Hoffmann, Torsten; Bös, Michael; Stadler, Heinz; Schnider, Patrick; Hunkeler, Walter; Godel, Thierry; Galley, Guido; Ballard, Theresa M.; Higgins, Guy A.; Poli, Sonia; Sleight, Andrew J.

doi:10.1016/j.bmcl.2005.11.047

Cited by 36 publications

(27 citation statements)

References 9 publications

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“…NTP, a selective and potent NK-1 receptor antagonist (Hoffmann et al, 2006), suppressed these effects of Sar-Met-SP. The results suggest that NK-1 receptors in sensory nerves, in addition to those at other sites such as the spinal cord and bladder smooth muscle may play an important role in the generation of overactive bladder and that block of these receptors may contribute to efficacy of NK-1 antagonists in the treatment of OAB.…”

Section: Discussionmentioning

confidence: 98%

“…NTP, which is a selective and potent NK-1 receptor antagonist with an EC 50 of approximately 10 nM (Hoffmann et al, 2006;Campi et al, 2010;Palea et al, 2010a,b), was tested at 200 and 500 nM concentrations. In bladder smooth muscle preparations, NTP in concentrations between 10 and 100 nM selectively suppresses the contractions evoked by an NK-1 agonist, but a high concentration (1 M) reduces the responses evoked by carbachol or KCl (Palea et al, 2010a,b).…”

Section: Nk-1 Receptors In Guinea Pig Drg Neurons 47mentioning

confidence: 99%

“…In the present experiments we examined the interactions between a selective NK-1 agonist (Sar-Met-SP) and a selective NK-1 antagonist, netupitant (NTP) (Hoffmann et al, 2006) on dissociated L6 and S1 DRG cells from female guinea pigs to determine whether the depressant effects of NTP on reflex bladder overactivity observed in anesthetized guinea pigs (Palea et al, 2010a,b) might be due to action on sensory neurons. Our experiments revealed that NTP blocks the various excitatory effects elicited by activation of NK-1 receptors in primary sensory neurons, raising the possibility that NK-1 receptors have a role in the generation of OAB symptoms and that block of these receptors may contribute to efficacy of NK-1 antagonists in the treatment of OAB.…”

Section: Introductionmentioning

confidence: 99%

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Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

Zhang

Pietra

Lovati

et al. 2012

J Pharmacol Exp Ther

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The suppression of overactive bladder symptoms in patients and overactive bladder reflexes in animal models by neurokinin (NK)-1 receptor antagonists raises the possibility that these drugs target sensory neurons. This mechanism was evaluated by examining the interactions between a specific NK-1 agonist, [Sar 9 ,Met(O 2 )(11)]-substance P (Sar-Met-SP), and a potent NK-1 antagonist, netupitant (NTP), on small size (20 -30 m) dissociated L6 and S1 dorsal root ganglion (DRG) neurons from female guinea pigs. Current-clamp recording revealed that SarMet-SP (1 M) elicited membrane depolarization (average 8.05 Ϯ 1.38 mV) in 27% (18 of 65) of DRG neurons. In 74% of the remaining neurons (35 of 47) Sar-Met-SP decreased the rheobase for action potential (AP) generation and increased the response to a suprathreshold stimulus (3 times rheobase) without changing the membrane potential. Sar-Met-SP also induced changes in the action potential (AP) wave form, including 1) an increase in overshoot (average 5 mV, n ϭ 35 neurons), 2) a prolongation of AP duration (from 4.64 to 5.29 ms, n ϭ 34), and 3) a reduction in the maximal rate of AP repolarization. NTP (200 nM) reversed the Sar-Met-SP-induced changes. Ca 2ϩ imaging showed that application of Sar-Met-SP (1 M) decreased the tachyphylaxis induced by repeated application of capsaicin (0.5 M), an effect blocked by pretreatment with NTP (200 nM). These results raise the possibility that activation of NK-1 receptors in primary sensory neurons plays a role in the generation of overactive bladder and that block of NK-1 receptors in these neurons may contribute to efficacy of NK-1 antagonists in the treatment of overactive bladder symptoms.

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Section: Discussionmentioning

confidence: 98%

Section: Nk-1 Receptors In Guinea Pig Drg Neurons 47mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

Zhang

Pietra

Lovati

et al. 2012

J Pharmacol Exp Ther

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“…Given the relevance of SP‐NK1 signaling in cancer, substantial efforts have been made to develop therapeutic inhibitors against NK1 (Huang and Korlipara, 2010; Munoz et al, 2011). Despite their promising results in model systems none of them has been shown to have potent antitumor activity in clinical trials (Humphrey, 2003; Hoffmann et al, 2006; Quartara and Altamura, 2006). Thus, we decided to target SP instead of its receptor and, given the lack of chemical compounds capable to inhibiting this small peptide, we used antibodies to address the therapeutic potential of SP inhibition in cancer.…”

mentioning

confidence: 99%

Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2

Mayordomo

García-Recio

Ametller

et al. 2012

Journal Cellular Physiology

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NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas. Despite the substantial efforts done to develop potent NK1 receptor antagonists, none of these antagonists had shown good antitumor activity in clinical trials. Now, we have tested the effect of inhibition of the neuropeptide Substance P (SP), a NK1 ligand, as a potential therapeutic approach in cancer. We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast, colon, and prostate cancer cell lines. These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway. Interestingly, in some cell lines SP abrogation decreased the steady state of Her2 and EGFR, suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors. In consequence, we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR. SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2, suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies. Thus, we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors, based in the immuno-blockade of the neuropeptide SP.

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“…The usefulness of these antagonists is limited in in vivo studies for the following reasons: their inability to gain access to the central nervous system through the blood-brain barrier, their neurotoxicity after administration in the central nervous system, their mast cell degranulation activity, their affinity is several orders of magnitude lower than that of natural agonists, their partial residual agonist activity, their metabolic instability, and their poor potency and ability to discriminate between tachykinin receptors. In the last two decades, nonpeptide based NK 1 receptor antagonists have been subjects of interest in many pharmaceutical companies, as reported in the literature [47][48][49][50]. An overview of the most wellknown NK 1 nonpeptide antagonists in the pharmaceutical scenario is reported in Table 17.1.…”

Section: Neurokinin 1 Antagonistsmentioning

confidence: 99%

Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

Perruccio

2013

Methods and Principles in Medicinal Chemistry

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Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists

Cited by 36 publications

References 9 publications

Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2

Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

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