Publications by authors named "Kirsten Morton"

10 Publications

  • Page 1 of 1

Novel benzamide-based histamine h3 receptor antagonists: the identification of two candidates for clinical development.

ACS Med Chem Lett 2015 Apr 13;6(4):450-4. Epub 2015 Mar 13.

Janssen Pharmaceutical Company, a division of Johnson & Johnson Pharmaceutical Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.

The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
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http://dx.doi.org/10.1021/ml5005156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394347PMC
April 2015

Synthesis and Pharmacological Characterization of Two Novel, Brain Penetrating P2X7 Antagonists.

ACS Med Chem Lett 2013 Apr 12;4(4):419-22. Epub 2013 Mar 12.

Janssen Research and Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.

The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be described. Both compounds are shown to be high potency P2X7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X7 blockade in animal models of neuro-inflammation.
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http://dx.doi.org/10.1021/ml400040vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027403PMC
April 2013

The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y₂ receptor.

Bioorg Med Chem Lett 2011 Sep 18;21(18):5552-6. Epub 2011 Jul 18.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC(50)) at the human Neuropeptide Y Y(2) receptor (NPY Y(2)). Six of the 23 analogs tested possessed an NPY Y(2) IC(50) ≤ 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.136DOI Listing
September 2011

Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement.

Psychopharmacology (Berl) 2011 May 22;215(1):191-203. Epub 2010 Dec 22.

Neuroscience, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA 92121, USA.

Rationale: Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.

Objective: The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.

Methods: Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.

Results: Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures.

Conclusions: Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.
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http://dx.doi.org/10.1007/s00213-010-2127-xDOI Listing
May 2011

Indole- and benzothiophene-based histamine H3 antagonists.

Bioorg Med Chem Lett 2010 Nov 27;20(21):6226-30. Epub 2010 Aug 27.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121-1126, United States.

Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
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http://dx.doi.org/10.1016/j.bmcl.2010.08.103DOI Listing
November 2010

Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: identification of candidates for clinical development.

Bioorg Med Chem Lett 2010 Jul 16;20(14):4210-4. Epub 2010 May 16.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
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http://dx.doi.org/10.1016/j.bmcl.2010.05.041DOI Listing
July 2010

Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists.

Bioorg Med Chem Lett 2010 May 20;20(9):2755-60. Epub 2010 Mar 20.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.

Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
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http://dx.doi.org/10.1016/j.bmcl.2010.03.071DOI Listing
May 2010

In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y(2) receptor.

Psychopharmacology (Berl) 2010 Feb 2;208(2):265-77. Epub 2009 Dec 2.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Rationale: The lack of potent, selective, brain penetrant Y(2) receptor antagonists has hampered in vivo functional studies of this receptor.

Objective: Here, we report the in vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a novel Y(2) receptor antagonist.

Methods: The affinity of JNJ-31020028 was determined by inhibition of the PYY binding to human Y(2) receptors in KAN-Ts cells and rat Y(2) receptors in rat hippocampus. The functional activity was determined by inhibition of PYY-stimulated calcium responses in KAN-Ts cells expressing a chimeric G protein Gqi5 and in the rat vas deferens (a prototypical Y(2) bioassay). Ex vivo receptor occupancy was revealed by receptor autoradiography. JNJ-31020028 was tested in vivo with microdialysis, in anxiety models, and on corticosterone release.

Results: JNJ-31020028 bound with high affinity (pIC(50) = 8.07 +/- 0.05, human, and pIC(50) = 8.22 +/- 0.06, rat) and was >100-fold selective versus human Y(1), Y(4), and Y(5) receptors. JNJ-31020028 was demonstrated to be an antagonist (pK(B) = 8.04 +/- 0.13) in functional assays. JNJ-31020028 occupied Y(2) receptor binding sites (approximately 90% at 10 mg/kg) after subcutaneous administration in rats. JNJ-31020028 increased norepinephrine release in the hypothalamus, consistent with the colocalization of norepinephrine and neuropeptide Y. In a variety of anxiety models, JNJ-31020028 was found to be ineffective, although it did block stress-induced elevations in plasma corticosterone, without altering basal levels, and normalized food intake in stressed animals without affecting basal food intake.

Conclusion: These results suggest that Y(2) receptors may not be critical for acute behaviors in rodents but may serve modulatory roles that can only be elucidated under specific situational conditions.
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http://dx.doi.org/10.1007/s00213-009-1726-xDOI Listing
February 2010

Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists.

Eur J Med Chem 2009 Nov 16;44(11):4413-25. Epub 2009 Jun 16.

Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States.

A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.
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http://dx.doi.org/10.1016/j.ejmech.2009.06.007DOI Listing
November 2009

Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study.

Thromb Haemost 2005 Oct;94(4):802-7

ZymoGenetics Inc, Seattle, WA 98102-3702, USA.

Factor XIII (FXIII) is a plasma transglutaminase that covalently cross-links fibrin proteins to one another and to other proteins, increasing the mechanical strength of blood clots. Endogenous FXIII is the final enzyme in the clotting cascade and circulates as a heterotetramer comprising 2 FXIII-A subunits and 2 FXIII-B subunits. Recombinant human FXIII A2 (rFXIII) homodimer is produced in Saccharomyces cerevisiae. Upon injection, rFXIII combines with the free FXIIIB subunit that circulates in excess to form the rA2B2 tetramer. In this placebo-controlled, double-blind, multi-dose study, the safety, pharmacokinetics, and pharmacodynamics of rFXIII were studied in 24 healthy volunteers, who were randomized in 2 cohorts of 12 subjects each. In each cohort, 8 subjects received 5 daily intravenous doses of rFXIII (10 or 25 U/kg), and 4 subjects received placebo. Recombinant FXIII was well tolerated. No deaths or serious adverse events occurred. The type and frequency of adverse events showed no pattern or dose response. No clinically significant changes in haematology, serum chemistry, or urinalysis laboratory values were observed. No clinical coagulopathy or thrombosis was observed. Recombinant FXIII did not produce any anti-yeast or anti-FXIII antibodies. After 5 daily doses of rFXIII, accumulation indices indicated a 3 to 4fold accumulation of rFXIII in plasma. The elimination half-life, estimated for rFXIII as the heterotetramer, ranged from 228-346 hours for the 10U/kg dose group and 167-197 hours for the 25U/kg dose group. The safety, pharmacokinetic, and immunogenic profile of rFXIII suggests it may have potential use in patients with congenital or acquired FXIII deficiency.
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http://dx.doi.org/10.1160/TH05-04-0292DOI Listing
October 2005