Publications by authors named "Raymond Rynberg"

11 Publications

  • Page 1 of 1

Heteroarylureas with fused bicyclic diamine cores as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2020 10 9;30(20):127463. Epub 2020 Aug 9.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2020.127463DOI Listing
October 2020

The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors.

Bioorg Med Chem Lett 2016 07 5;26(13):3109-3114. Epub 2016 May 5.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.

The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.001DOI Listing
July 2016

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279.

ACS Med Chem Lett 2015 Dec 2;6(12):1204-8. Epub 2015 Nov 2.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.

The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677372PMC
December 2015

Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2014 Feb 6;24(3):737-41. Epub 2014 Jan 6.

Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.
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http://dx.doi.org/10.1016/j.bmcl.2013.12.113DOI Listing
February 2014

Pyrazole-based arylalkyne cathepsin S inhibitors. Part III: modification of P4 region.

Bioorg Med Chem Lett 2013 Feb 21;23(4):1070-4. Epub 2012 Dec 21.

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

Novel classes of tetrahydropyrido-pyrazole thioether amines and arylalkynes that display potency against human Cathepsin S have been previously reported. Here, key pharmacophoric elements of these two classes are merged, and SAR investigations of the P4 region are described, in conjunction with re-optimization of the P5 and P1/P1'/P3 regions. Identification of meta-substituted arylalkynes with good potency and improved solubility is described.
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http://dx.doi.org/10.1016/j.bmcl.2012.12.014DOI Listing
February 2013

Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat, Dog, and Primate.

ACS Med Chem Lett 2012 Oct 22;3(10):823-7. Epub 2012 Aug 22.

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

A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatty acid amides: anandamide, oleoyl ethanolamide, and palmitoyl ethanolamide, in the rat, dog, and cynomolgous monkey. The elevation of the levels of these lipids in the plasma of monkeys suggests that FAAH-2 may not play a significant role in regulating plasma levels of fatty acid ethanolamides in primates.
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http://dx.doi.org/10.1021/ml300186gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025847PMC
October 2012

1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines as TRPV1 antagonists with improved properties.

Bioorg Med Chem Lett 2010 Dec 7;20(23):7142-6. Epub 2010 Sep 7.

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

Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 ≥237 μg/mL and SIF=11 μg/mL) was significantly improved over compound 1 (pH 2=5 μg/mL and SIF=0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.
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http://dx.doi.org/10.1016/j.bmcl.2010.09.006DOI Listing
December 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

Practical synthesis of a Cathepsin S inhibitor: route identification, purification strategies, and serendipitous discovery of a crystalline salt form.

J Org Chem 2010 Mar;75(6):1940-7

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

A "redox economical" strategy resulted in a concise, modular synthesis of compound 1, a potent Cathepsin S inhibitor. Starting from three building blocks, crude drug substance was prepared in a two-step sequence in high yield. Efficient purification of the crude drug substance was accomplished via the formation of an unusual monoethyl oxalate salt.
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http://dx.doi.org/10.1021/jo902650bDOI Listing
March 2010

Identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidine derivatives as TRPV1 antagonists.

Bioorg Med Chem Lett 2009 Jan 13;19(1):40-6. Epub 2008 Nov 13.

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

We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure-activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED(50)=0.5mg/kg in rats.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.024DOI Listing
January 2009

2-Aryl benzimidazoles featuring alkyl-linked pendant alcohols and amines as inhibitors of checkpoint kinase Chk2.

Bioorg Med Chem Lett 2007 Dec 4;17(23):6467-71. Epub 2007 Oct 4.

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

A series of benzimidazole compounds containing pendant alcohol and amine moieties was found to be active against checkpoint kinase Chk2. These compounds were prepared to examine a potential hydrogen bond interaction with an active site residue and to investigate replacement of a biaryl linker with an aliphatic system in an effort to improve solubility.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.098DOI Listing
December 2007