Publications by authors named "Richard Apodaca"

13 Publications

  • Page 1 of 1

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

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

1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2014 Mar 31;24(5):1280-4. Epub 2014 Jan 31.

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

A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.
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http://dx.doi.org/10.1016/j.bmcl.2014.01.064DOI Listing
March 2014

Mobile apps for chemistry in the world of drug discovery.

Drug Discov Today 2011 Nov 6;16(21-22):928-39. Epub 2011 Sep 6.

Royal Society of Chemistry, Wake Forest, NC 27587, USA.

Mobile hardware and software technology continues to evolve very rapidly and presents drug discovery scientists with new platforms for accessing data and performing data analysis. Smartphones and tablet computers can now be used to perform many of the operations previously addressed by laptops or desktop computers. Although the smaller screen sizes and requirements for touch-screen manipulation can present user-interface design challenges, especially with chemistry-related applications, these limitations are driving innovative solutions. In this early review of the topic, we collectively present our diverse experiences as software developer, chemistry database expert and naïve user, in terms of what mobile platforms could provide to the drug discovery chemist in the way of applications in the future as this disruptive technology takes off.
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http://dx.doi.org/10.1016/j.drudis.2011.09.002DOI Listing
November 2011

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

Diamine-based human histamine H3 receptor antagonists: (4-aminobutyn-1-yl)benzylamines.

Eur J Med Chem 2009 Oct 13;44(10):4098-106. Epub 2009 May 13.

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

A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R(3)R(4)N-); (2) the benzylamine moiety (R(1)R(2)N-); and (3) the point of attachment of the benzylamine group (R(1)R(2)N- in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H(3) antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H(3) binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.
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http://dx.doi.org/10.1016/j.ejmech.2009.04.049DOI Listing
October 2009

Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase.

Anesth Analg 2009 Jan;108(1):316-29

Pain and Related Disorders, Johnson and Johnson Pharmaceutical Research and Development, LLC, San Diego, California 92121, USA.

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family. It catalyzes the hydrolysis of several endogenous biologically active lipids, including anandamide (arachidonoyl ethanolamide), oleoyl ethanolamide, and palmitoyl ethanolamide. These endogenous FAAH substrates have been shown to be involved in a variety of physiological and pathological processes, including synaptic regulation, regulation of sleep and feeding, locomotor activity, pain and inflammation. Here we describe the biochemical and biological properties of a potent and selective FAAH inhibitor, 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide (JNJ-1661010). The time-dependence of apparent IC(50) values at rat and human recombinant FAAH, dialysis and mass spectrometry data indicate that the acyl piperazinyl fragment of JNJ-1661010 forms a covalent bond with the enzyme. This bond is slowly hydrolyzed, with release of the piperazinyl fragment and recovery of enzyme activity. The lack of inhibition observed in a rat liver esterase assay suggests that JNJ-1661010 is not a general esterase inhibitor. JNJ-1661010 is >100-fold preferentially selective for FAAH-1 when compared to FAAH-2. JNJ-1661010 dose-dependently increases arachidonoyl ethanolamide, oleoyl ethanolamide, and palmitoyl ethanolamide in the rat brain. The compound attenuates tactile allodynia in the rat mild thermal injury model of acute tissue damage and in the rat spinal nerve ligation (Chung) model of neuropathic pain. JNJ-1661010 also diminishes thermal hyperalgesia in the inflammatory rat carrageenan paw model. These data suggest that FAAH inhibitors with modes of action similar to JNJ-1661010 may be useful clinically as broad-spectrum analgesics.
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http://dx.doi.org/10.1213/ane.0b013e31818c7cbdDOI Listing
January 2009

Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2008 Sep 25;18(17):4838-43. Epub 2008 Jul 25.

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

A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented.
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http://dx.doi.org/10.1016/j.bmcl.2008.07.081DOI Listing
September 2008

Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling.

Bioorg Med Chem 2008 Mar 25;16(6):2968-73. Epub 2007 Dec 25.

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

Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
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http://dx.doi.org/10.1016/j.bmc.2007.12.048DOI Listing
March 2008

Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase.

J Med Chem 2007 Mar 6;50(5):1058-68. Epub 2007 Feb 6.

Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the K(i) follows a well-defined correlation with the Hammett sigma(p) constant (rho = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K(i)s as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.
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http://dx.doi.org/10.1021/jm0611509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2531193PMC
March 2007

Aplysamine-1 and related analogs as histamine H3 receptor antagonists.

Bioorg Med Chem Lett 2006 Feb 21;16(4):897-900. Epub 2005 Nov 21.

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

Aplysamine-1 (1), a marine natural product, was synthesized and screened for in vitro activity at the human and rat histamine H3 receptors. Aplysamine-1 (1) was found to possess a high binding affinity for the human H3 receptor (Ki = 30+/-4 nM). Synthetic analogs of 1, including des-bromoaplysamine-1 (10) and dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-ethyl}-amine (13), were potent H3 antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2005.11.003DOI Listing
February 2006

4-phenoxypiperidines: potent, conformationally restricted, non-imidazole histamine H3 antagonists.

J Med Chem 2005 Mar;48(6):2229-38

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

Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.
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http://dx.doi.org/10.1021/jm049212nDOI Listing
March 2005

A new class of diamine-based human histamine H3 receptor antagonists: 4-(aminoalkoxy)benzylamines.

J Med Chem 2003 Aug;46(18):3938-44

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

4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H(3) receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be antagonists in a cell-based model of human histamine H(3) receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H(3) receptor antagonist.
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http://dx.doi.org/10.1021/jm030185vDOI Listing
August 2003