Discovery of novel, orally active dual NK1/NK2 antagonists

Bernstein, Peter R; Aharony, David; Albert, Jeffrey S.; Andisik, Donald W.; Barthlow, Herbert; Bialecki, Russell; Davenport, T. W.; Dedinas, Robert F.; Dembofsky, Bruce T.; Koether, Gerard M.; Kosmider, Benedict J.; Kirkland, Karin; Ohnmacht, Cyrus J.; Potts, William; Rumsey, William L.; Shen, Lihong; Shenvi, Ashok B.; Sherwood, Scott; Stollman, David; Russell, Keith

doi:10.1016/s0960-894x(01)00572-8

Cited by 39 publications

(27 citation statements)

References 13 publications

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“…The selective NK 1 R antagonists CP-99994 (McLean et al, 1993) and aprepitant (Hale et al, 1998) and the pan-NK receptor antagonist ZD6021 (Bernstein et al, 2001) were synthesized at AstraZeneca (Mölndal, Sweden).…”

Section: Methodsmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Lindström¹,

Mentzer²,

Påhlman³

et al. 2007

J Pharmacol Exp Ther

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We compared the neurokinin 1 receptor (NK 1 R) antagonists aprepitant, CP-99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-methyl]napthamide]] with respect to receptor interactions and duration of efficacy in vivo. In Ca 2ϩ mobilization assays (fluorometric imaging plate reader), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP). In reversibility studies, antagonists were present for 30 min before washing, and responses to SP were repeatedly measured afterward. The compounds were administered i.p. to gerbils, and the gerbil foot tap (GFT) response was monitored at various time points. The NK 1 R receptor occupancy for aprepitant was determined in striatal regions. Levels of compound in brain and plasma were measured. Antagonists were equipotent at human NK 1 R and acted competitively with SP. After preincubation, aprepitant and ZD6021 attenuated the maximal responses, whereas CP-99994 only shifted the SP concentration-response curve to the right. The inhibitory effect of CP-99994 was over within 30 min, whereas for ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced maximal inhibition lasting at least 60 min. CP-99994 (3 mol/kg) inhibited GFT by 100% 15 min after administration, but the effect declined rapidly together with brain levels thereafter. The efficacy of ZD6021 (10 mol/kg) lasted 4 h and correlated well with brain levels. Aprepitant (3 mol/kg) inhibited GFT and occupied striatal NK 1 R by 100% for Ͼ48 h despite that brain levels of compound were below the limit of detection after 24 h. Slow functional reversibility is associated with long-lasting in vivo efficacy of NK 1 R antagonists, whereas the efficacy of compounds with rapid reversibility is reflected by their pharmacokinetics.The neurokinins substance P (SP), neurokinin (NK) A (NKA), and NKB belong to the tachykinin peptide family (Severini et al., 2002). The tachykinin receptors are divided into three subtypes: NK 1 R, NK 2 R, and NK 3 R. The rank order of potency of the endogenous tachykinins are: for NK 1 R, SP Ն NKA Ͼ NKB; for NK 2 R, NKA Ͼ NKB Ͼ SP; and for NK 3 R, NKB Ͼ NKA Ͼ SP (for review, see Pennefather et al., 2004). Hemokinin-1 and endokinins A and B are relatively new mammalian members of the tachykinin family but appear to have similar receptor pharmacology as SP (Page, 2006). On the other hand, endokinins C and D have negligible affinity for known NK receptors (Page, 2006).Preclinical research has implicated especially the NK 1 R as being involved in several pathological disorders, including emesis, asthma, psychiatric disorders, gastrointestinal disorders, pain, migraine, inflammation, and urinary bladder disorders. This has led to the subsequent development of selective and potent NK 1 R antagonists (for recent review, see Quartara and Altamura, 2006). However, so far, only aprepitant has reached the market for treatment of chemothe...

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Section: Methodsmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Lindström¹,

Mentzer²,

Påhlman³

et al. 2007

J Pharmacol Exp Ther

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“…Substitution at 2-naphthalene position increases NK 1 potency while alterations in piperidine region increases the NK 2 potency. Thus factors affecting the balance of NK 1 and NK 2 selectivity are identified and several dual acting antagonists have now been developed [135,[260][261][262][263][264][265][266]. Boks et.…”

Section: Non-peptide Antagonistsmentioning

confidence: 99%

Substance P: Structure, Function, and Therapeutics

Datar

Srivastava²,

Coutinho³

et al. 2004

CTMC

148

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Extensive efforts since 1931, on the structural determination of the mammalian tachykinin SP by NMR, CD and IR have turned out to be inconclusive. Studies are now being concentrated on the structural properties and characteristics of various NK receptors (NK(1), NK(2) and NK(3)) with the help of genetics, cloning, receptor engineering, mutagenesis and modeling. This knowledge is now being fruitfully used in the development of non-peptide NK(1) receptor antagonists that essentially block the pharmacological effects of SP. It is now being realized that the simultaneous blockade of two or more receptors gives promising results in emesis, depression and pulmonary obstructive diseases. In addition to the synthetic compounds, the discovery of antagonists from natural origin has added a great value to this field. In this review we have made an attempt to present the structural characteristics of SP, its analogs and antagonists, the structural characteristics of the NK receptor, and structure activity relationships that have helped to improve the therapeutic utilities of SP antagonists.

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“…Indeed, areas of bladder inflammation are found during chronic implantation of catheters (22,88), as an integrative part of bladder responses to intravesical bacillus Calmette-Guerin (BCG) (10,12) and capsaicin therapy (34), during radiation cystitis, and in cyclophosphamide-induced cystitis (86,87), interstitial cystitis (28,68), and bladder cancer (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

“…Alternatively, several dual antagonists of NK1Rs and NK2Rs have been developed (67,77). With the exception of ZD-6021, which has been shown to dose dependently attenuate plasma extravasation in guinea pigs (6), little if any investigation of the therapeutic potential of dual antagonists has been done. Alternatively, several authors have used a combination of NK 1 , NK 2 , and NK 3 antagonists to reduce visceral hyperalgesia (44).…”

mentioning

confidence: 99%

Mast cells mediate substance P-induced bladder inflammation through an NK₁receptor-independent mechanism

Saban

Gerard

Saban

et al. 2002

American Journal of Physiology-Renal Physiology

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The role of neurokinin-1 receptors (NK1R) in the interaction between mast cells and substance P (SP) in bladder inflammation was determined. Mast cell-deficient Kit(W)/Kit(W-v), congenic normal (+/+), and Kit(W)/Kit(W-v) mice that were reconstituted with bone marrow cells isolated from NK1R(-/-) mice were challenged by instillation of SP, antigen, or saline into the urinary bladder. Twenty-four hours after challenge, the bladders were prepared for morphological assessment and gene expression. SP-induced bladder inflammation was mast cell dependent and did not require NK1R expression on the mast cell. Cluster analysis identified functionally significant genes that were dependent on the presence of mast cells for their upregulation regardless of stimulus. Those include serine protein inhibitor 2.2, maspin, mitogen- and stress-activated protein kinase 2, and macrophage colony-stimulating factor 1. Our findings demonstrate that while mast cells are essential for both antigen- and SP-induced bladder inflammation, there are common genes and unique genes expressed in each type of inflammatory reaction. When combined with unique animal models, gene array analysis provides a useful approach for identifying and characterizing pathways involved in bladder inflammation.

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Discovery of novel, orally active dual NK1/NK2 antagonists

Cited by 39 publications

References 13 publications

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Substance P: Structure, Function, and Therapeutics

Mast cells mediate substance P-induced bladder inflammation through an NK₁receptor-independent mechanism

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Discovery of novel, orally active dual NK1/NK2 antagonists

Cited by 39 publications

References 13 publications

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Substance P: Structure, Function, and Therapeutics

Mast cells mediate substance P-induced bladder inflammation through an NK1receptor-independent mechanism

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Product

Resources

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Mast cells mediate substance P-induced bladder inflammation through an NK₁receptor-independent mechanism