Publications by authors named "Daniel J Buzard"

13 Publications

  • Page 1 of 1

C-H activation reactions as useful tools for medicinal chemists.

Bioorg Med Chem Lett 2016 11 11;26(22):5378-5383. Epub 2016 Aug 11.

Medicinal Chemistry, Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92102, USA.

In recent years, there has been an exponential rise in the number of reports describing synthetic methods that utilize catalytic sp and sp C-H bond activation. Many have emerged as powerful synthetic tools for accessing biologically active motifs. Indeed, application to C-C and C-heteroatom bond formation, provides new directives for the construction of new pharmaceutical entities. Herein, we highlight some recent novel C-H activation processes that exemplify the utility of these transformations in medicinal chemistry.
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http://dx.doi.org/10.1016/j.bmcl.2016.06.036DOI Listing
November 2016

Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series.

Bioorg Med Chem Lett 2015 Aug 23;25(15):3034-8. Epub 2015 May 23.

Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.
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http://dx.doi.org/10.1016/j.bmcl.2015.04.102DOI Listing
August 2015

Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor.

Bioorg Med Chem Lett 2015 Feb 9;25(3):659-63. Epub 2014 Dec 9.

Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.

Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.
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http://dx.doi.org/10.1016/j.bmcl.2014.11.089DOI Listing
February 2015

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists.

ACS Med Chem Lett 2014 Dec 25;5(12):1334-9. Epub 2014 Nov 25.

Arena Pharmaceuticals, Inc. , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.

S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.
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http://dx.doi.org/10.1021/ml500422mDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265824PMC
December 2014

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor.

ACS Med Chem Lett 2014 Dec 4;5(12):1313-7. Epub 2014 Nov 4.

Arena Pharmaceuticals, Inc. , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
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http://dx.doi.org/10.1021/ml500389mDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265817PMC
December 2014

Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists.

Bioorg Med Chem Lett 2014 Sep 3;24(17):4332-5. Epub 2014 Jul 3.

Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.

A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.
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http://dx.doi.org/10.1016/j.bmcl.2014.06.071DOI Listing
September 2014

Kinetics of 5-HT2B receptor signaling: profound agonist-dependent effects on signaling onset and duration.

J Pharmacol Exp Ther 2013 Dec 18;347(3):645-59. Epub 2013 Sep 18.

Departments of Receptor Pharmacology (D.J.U., X.C., J.G., T.L.A., S.C., H.T.-M.D., J.F., M.K.L., C.X., I.G.), Chemistry (D.J.B.), Drug Metabolism & Pharmacokinetics (C.C., A.J.M.S.), Arena Pharmaceuticals Inc., San Diego, California.

The kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptor-mediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine2B (5-HT2B) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from Gαq-mediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signal-regulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds.
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http://dx.doi.org/10.1124/jpet.113.207670DOI Listing
December 2013

Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists.

J Med Chem 2013 Nov 8;56(21):8224-56. Epub 2013 Aug 8.

Department of Medicinal Chemistry, Arena Pharmaceuticals , 6166 Nancy Ridge Drive, San Diego, California 92121, United States.

The cannabinoid receptor type 2 (CB2) is a class A GPCR that was cloned in 1993 while looking for an alternative receptor that could explain the pharmacological properties of Δ(9)-tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system. In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, peripheral nervous system, and gastrointestinal tract. Several "mixed" cannabinoid agonists are currently in clinical use primarily for controlling pain, and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects. Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this Perspective, we seek to provide a concise update of progress in the field.
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http://dx.doi.org/10.1021/jm4005626DOI Listing
November 2013

GPR119 agonists 2009-2011.

Pharm Pat Anal 2012 Jul;1(3):285-99

Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA.

The increasing incidence of Type II diabetes mellitus worldwide continues to attract the attention and resources of the pharmaceutical industry in the pursuit of more effective therapies for blood glucose control. New approaches that compare favorably with classical medicaments while avoiding hypoglycemic episodes or waning effectiveness are paramount. Recent advances toward this end have been realized based on the biology of the glucagon like peptide-1 receptor (GLP1R). This β-cell-expressed GPCR has the ability to promote insulin release in a glucose-dependent fashion, and has been shown to elicit improved glycemic control and preservation of β-cell mass. Direct activation of GLP1R utilizing peptide mimetics has been achieved; however, attempts to access the biology of this receptor via small-molecule approaches have thus far been elusive. In this context, GPR119 has emerged as a tractable new alternative to GLP1R. GPR119 is another GPCR expressed on the β-cell, which, like GLP1R, signals in a glucose-dependent manner. Moreover, GPR119-mediated increases in GLP-1 and other incretins upon activation in the intestine further increase the insulinotropic activity of the β-cell. The early success in identifying small-molecule agonists of the GPR119 has prompted a rapid increase in the number of patent applications filed in the last few years. In this review we provide a comprehensive summary of all patent activity in this field that has appeared within the 2009-2011 timeframe.
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http://dx.doi.org/10.4155/ppa.12.33DOI Listing
July 2012

Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease.

Bioorg Med Chem Lett 2012 Jul 7;22(13):4404-9. Epub 2012 May 7.

Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA.

Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.
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http://dx.doi.org/10.1016/j.bmcl.2012.04.129DOI Listing
July 2012

Agonist/antagonist modulation in a series of 2-aryl benzimidazole H4 receptor ligands.

Bioorg Med Chem Lett 2010 Jun 11;20(11):3367-71. Epub 2010 Apr 11.

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

The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.017DOI Listing
June 2010

GPR119 agonists for the treatment of type 2 diabetes.

Expert Opin Ther Pat 2009 Oct;19(10):1339-59

Departments of Medicinal Chemistry & Metabolic Disorders, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA.

Background: Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially nerves and blood vessels. Diabetes causes about 5% of all deaths globally each year and is likely to increase by > 50% in the next 10 years without urgent action. In light of these alarming statistics, the pharmaceutical industry has been on a quest to characterize more promising molecular targets to satisfy stringent new criteria for anti-hyperglycemic agents introduced by the American Diabetes Association. On to this stage, G-protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium.

Objective: In this review, we outline the current clinical trial landscape and paint a detailed illustration of the key structural information realized from GPR119 agonist campaigns that have recently emerged in the Patent Cooperation Treaty literature.

Conclusion: GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels in vivo. As a stand-alone therapy or in tandem with approved DPP-IV inhibitors, they could herald a brand new treatment paradigm for type 2 diabetes mellitus. With the passage of the first GPR119 agonist clinical candidates into Phase I trials (Arena/Ortho McNeil APD597; Metabolex MBX-2982; Prosidion/OSI PSN821) and confirmatory reports of clinical proof of concept with respect to glycemic control and incretin release, the spotlight has been set for this new class of therapeutic.
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http://dx.doi.org/10.1517/13543770903153878DOI Listing
October 2009

Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands.

Bioorg Med Chem Lett 2006 Dec 20;16(23):6043-8. Epub 2006 Sep 20.

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

A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.
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http://dx.doi.org/10.1016/j.bmcl.2006.08.117DOI Listing
December 2006