Publications by authors named "Kiev S Ly"

13 Publications

  • Page 1 of 1

Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate.

J Med Chem 2015 Jul 8;58(14):5620-36. Epub 2015 Jul 8.

The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00742DOI Listing
July 2015

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

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

Synthesis of a histamine H(3) receptor antagonist-manipulation of hydroxyproline stereochemistry, desymmetrization of homopiperazine, and nonextractive sodium triacetoxyborohydride reaction workup.

J Org Chem 2010 Jul;75(13):4463-71

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

We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H(3) receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
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http://dx.doi.org/10.1021/jo100629zDOI 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

Novel imidazole-based histamine H3 antagonists.

Bioorg Med Chem Lett 2009 Feb 6;19(3):903-7. Epub 2008 Dec 6.

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

A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.114DOI Listing
February 2009

2-Aryloxymethylmorpholine histamine H(3) antagonists.

Bioorg Med Chem Lett 2008 Nov 24;18(21):5796-9. Epub 2008 Sep 24.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., San Diego, CA 92121-1126, USA.

The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.077DOI Listing
November 2008

Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2008 Jan 13;18(1):39-43. Epub 2007 Nov 13.

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

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2007.11.016DOI Listing
January 2008

Novel naphthyridines are histamine H3 antagonists and serotonin reuptake transporter inhibitors.

Bioorg Med Chem Lett 2007 May 4;17(9):2566-9. Epub 2007 Feb 4.

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

A series of novel tetrahydronaphthyridine-based histamine H(3) ligands that have serotonin reuptake transporter inhibitor activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyridine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.02.006DOI Listing
May 2007

Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Feb 16;17(4):1047-51. Epub 2006 Nov 16.

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

A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H(3) ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.036DOI Listing
February 2007

Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore.

Bioorg Med Chem Lett 2007 Feb 2;17(3):702-6. Epub 2006 Nov 2.

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

A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.089DOI Listing
February 2007

Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.

J Med Chem 2005 Dec;48(26):8289-98

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

Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
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http://dx.doi.org/10.1021/jm0502081DOI Listing
December 2005

The first potent and selective non-imidazole human histamine H4 receptor antagonists.

J Med Chem 2003 Sep;46(19):3957-60

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

Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.
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http://dx.doi.org/10.1021/jm0341047DOI Listing
September 2003