Douglas W P Hay

Publications (10)48.46 Total impact

• Article: Pharmacological Characterization of GSK573719 (Umeclidinium): A Novel, Long-Acting, Inhaled Antagonist of the Muscarinic Cholinergic Receptors for Treatment of Pulmonary Diseases.

  Michael Salmon, Mark A Luttmann, James J Foley, Peter T Buckley, Dulcie B Schmidt, Miriam Burman, Edward F Webb, Christopher J Dehaas, Charles J Kotzer, Victoria J Barrett, Robert J Slack, Henry M Sarau, Michael R Palovich, Dramane I Laine, Douglas W P Hay, William L Rumsey
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  ABSTRACT: Activation of M3 muscarinic cholinergic receptors (mAChR) increases airway tone whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719, 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane (umeclidinium). The affinity (K(i)) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05-0.16 nM. Dissociation of [(3)H]-GSK573719 from the M3 mAChR was slower than that for the M2 mAChR; t(1/2) values = 82 and 9 min, respectively. In CHO cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated pM potency (-log pA(2) = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug wash-out. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA(2) = 316 pM) vs carbachol and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 min (vs 413 min for tiotropium bromide). In mice, the ED(50) value was 0.02 μg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose-dependently blocked Ach-induced bronchoconstriction with long duration of action and was comparable to tiotropium; 2.5 μg elicited 50% bronchoprotection for >24h. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into 24h duration of bronchodilation in vivo which suggested umeclidinium will be a once-daily inhaled treatment for pulmonary diseases.
  Journal of Pharmacology and Experimental Therapeutics 02/2013; · 3.83 Impact Factor
• Article: Targeted Disruption of the Endothelin-B-Receptor Gene Attenuates Inflammatory Nociception and Cutaneous Inflammation in Mice

  Don E. Griswold, Stephen A Douglas, Lenox D. Martin, Gregg T. Davis, Laura Davis, Zhaohui Ao, Mark A. Luttmann, Mark Pullen, Ponnal Nambi, Douglas W.P. Hay, Eliot H. Ohlstein
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  ABSTRACT: Endothelin-1 (ET-1) has been suggested to have a potential function as an inflammatory mediator. The study reported here assessed the putative inflammatory/nociceptive actions of the ET isopeptides using endothelin-B (ETB)-receptor knockout (KO) mice and ETA- (SB 234551) and ETB- (A192621) selective antagonists. Phenylbenzoquinone (PBQ)-induced algesia was evident in the wild-type (WT) ETB (+/+) mice, attenuated by 80% in the heterozygous ETB (+/-) mice, and absent in the ETB (-/-) homozygotes. This was reproduced pharmacologically in WT ETB (+/+) mice where the algesic effect of PBQ was inhibited 74% by A192621, but unaffected by SB 234551 (both at 25 mg/kg p.o.). Similar observations were made in a model of cutaneous inflammation: ETB (+/+) mice had a marked inflammatory response to topical arachidonic acid, ETB (+/-) and ETB (-/-) mice had significantly reduced edema responses (37% and 65% inhibition). Neutrophil infiltration was reduced in the ETB (+/-) and ETB (-/-) mice (51% and 65% reduction, respectively). Topical administration of A192621 (500 [mu]g/ear) inhibited arachidonic acid-induced swelling (39%) in WT ETB (+/+) mice. Collectively, these results support a role for the ETB-receptor in the mediation of inflammatory pain and cutaneous inflammatory responses. As such, the development of ETB-receptor-selective antagonists may be of therapeutic utility in the treatment of inflammatory disorders. (C) 2000 Lippincott Williams & Wilkins, Inc.
  Journal of Cardiovascular Pharmacology 08/2012; 36. · 2.29 Impact Factor
• Article: Human urotensin‐II is a potent spasmogen of primate airway smooth muscle

  Douglas W P Hay, Mark A Luttmann, Stephen A Douglas
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  ABSTRACT: The contractile profile of human urotensin-II (hU-II) was examined in primate airway and pulmonary vascular tissues. hU-II contracted tissues from different airway regions with similar potencies (pD2s from 8.6 to 9.2). However, there were regional differences in the efficacy of hU-II, with a progressive increase in the maximum contraction from trachea to smaller airway regions (from 9 to 41% of the contraction to 10 μM carbachol). hU-II potently contracted pulmonary artery tissues from different regions with similar potencies and efficacies: pD2s=8.7 to 9.3 and maximal contractions=79 to 86% of 60 mM KCl. hU-II potently contracted pulmonary vein preparations taken proximal to the atria, but had no effect in tissues from distal to the atria. This is the first report describing the contractile activity of hU-II in airways and suggests that the potential pathophysiological role of this peptide in lung diseases warrants investigation.British Journal of Pharmacology (2000) 131, 10–12; doi:10.1038/sj.bjp.0703533
  British Journal of Pharmacology 01/2009; 131(1):10 - 12. · 4.41 Impact Factor
• Article: A novel role for tachykinin neurokinin-3 receptors in regulation of human bronchial Ganglia neurons.

  Allen C Myers, Roy G Goldie, Douglas W P Hay
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  ABSTRACT: The neuropeptide tachykinins and their receptors have been implicated in the pathogenesis of lung disease, although the role of the tachykinin neurokinin-3 receptor has not been elucidated. Using confocal microscopy, we identified tachykinin neurokinin-3 receptors on human bronchial parasympathetic ganglion neurons. Electrophysiologic recordings demonstrated that activation of sensory nerve fibers, either by antidromic stimulation or capsaicin, depolarized these neurons. This response was mimicked by exogenously applied tachykinin neurokinin-3 receptor-selective agonist, senktide analogue, but not significantly by tachykinin neurokinin-1 or neurokinin-2 receptor-selective agonists. Responses to endogenous tachykinins or exogenous selective tachykinin neurokinin-3 receptor activation with senktide analogue were inhibited by the selective tachykinin neurokinin-3 receptor antagonists, SB 223412 or SB 235375. We provide the first evidence that tachykinin neurokinin-3 receptors regulate human bronchial parasympathetic ganglion neurotransmission by activation of a peripheral reflex. This pathway may play a significant role in controlling bronchomotor tone and air flow to the lung.
  American Journal of Respiratory and Critical Care Medicine 03/2005; 171(3):212-6. · 11.08 Impact Factor
• Article: A Highly Convergent Synthesis of 2‐Phenyl Quinoline as Dual Antagonists for NK2 and NK3 Receptors

  Hongxing Yan, Jeffrey K. Kerns, Qi Jin, Chongjie Zhu, Mary S. Barnette, James F. Callahan, Douglas W. P. Hay, Larry J. Jolivette, Mark A. Luttmann, Henry M. Sarau, Keith W. Ward, Katherine L. Widdowson, Zehong Wan
  Synthetic Communications 01/2005; 35(24):3105-3112. · 1.06 Impact Factor
• Article: A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit.

  Patricia L Podolin, Brian J Bolognese, James J Foley, Dulcie B Schmidt, Peter T Buckley, Katherine L Widdowson, Qi Jin, John R White, Judithann M Lee, Richard B Goodman, Tonja R Hagen, Osamu Kajikawa, Lisa A Marshall, Douglas W P Hay, Henry M Sarau
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  ABSTRACT: Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits (125)I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC(50) = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC(50) = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-alpha, IL-8, PGE(2), leukotriene B(4), and leukotriene C(4) levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-alpha and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC(50) = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.
  The Journal of Immunology 12/2002; 169(11):6435-44. · 5.79 Impact Factor
• Article: Nonpeptide tachykinin receptor antagonists. III. SB 235375, a low central nervous system-penetrant, potent and selective neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.

  Douglas W P Hay, Giuseppe A M Giardina, Don E Griswold, David C Underwood, Charles J Kotzer, Brian Bush, William Potts, Punam Sandhu, Dave Lundberg, James J Foley, Dulcie B Schmidt, Lenox D Martin, David Kilian, Jeffrey J Legos, Frank C Barone, Mark A Luttmann, Mario Grugni, Luca F Raveglia, Henry M Sarau
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  ABSTRACT: In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited (125)I-[MePhe(7)]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K(i) = 2.2 nM and antagonized competitively NKB-induced Ca(2+) mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K(b) = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA(2) = 8.1) and guinea pig ileal circular smooth muscles (pA(2) = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K(i) > 100,000 nM) and hNK-2 receptors (K(i) = 209 nM), and was without effect, at 1 microM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED(50) of 0.56 mg/kg). Intraperitoneal SB 235375 (10-30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3-30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system.
  Journal of Pharmacology and Experimental Therapeutics 01/2002; 300(1):314-23. · 3.83 Impact Factor
• Article: Stepwise Modulation of Neurokinin-3 and Neurokinin-2 Receptor Affinity and Selectivity in Quinoline Tachykinin Receptor Antagonists

  Frank E. Blaney, Luca F. Raveglia, Marco Artico, Stefano Cavagnera, Catherine Dartois, Carlo Farina, Mario Grugni, Stefania Gagliardi, Mark A. Luttmann, Marisa Martinelli, Guy M. M. G. Nadler, Carlo Parini, Paola Petrillo, Henry M. Sarau, Mark A. Scheideler, Douglas W. P. Hay, Giuseppe A. M. Giardina
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  ABSTRACT: A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described. Docking studies with 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemical design and speed up the identification of potent and combined antagonsits at both receptors. (S)-(+)-N-(1-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238:  hNK-3R binding affinity, Ki = 0.8 nM; hNK-2R binding affinity, Ki = 0.8 nM) emerged as the best example in this approach. Further studies led to the identification of (S)-(+)-N-(1,2,2-trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240:  hNK-3R binding affinity, Ki = 193 nM; hNK-2R binding affinity, Ki = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 2-phenylquinoline chemical class. Since some members of this chemical series showed a significant binding affinity for the human μ-opioid receptor (hMOR), docking studies were also conducted on a 3-D model of the hMOR, resulting in the identification of a viable chemical strategy to avoid any significant μ-opioid component. Compounds 25 and 28 are therefore suitable pharmacological tools in the tachykinin area to elucidate further the pathophysiological role of NK-3 and NK-2 receptors and the therapeutic potential of selective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.
  Journal of Medicinal Chemistry 04/2001; 44(11). · 5.25 Impact Factor
• Article: Discovery of a Novel Class of Selective Non-Peptide Antagonists for the Human Neurokinin-3 Receptor. 2. Identification of (S)-N-(1-Phenylpropyl)-3-hydroxy-2- phenylquinoline-4-carboxamide (SB 223412)†

  Giuseppe A. M. Giardina, Luca F. Raveglia, Mario Grugni, Henry M. Sarau, Carlo Farina, Andrew D. Medhurst, Davide Graziani, Dulcie B. Schmidt, Roberto Rigolio, Mark Luttmann, Stefano Cavagnera, James J. Foley, Vittorio Vecchietti, Douglas W. P. Hay
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  ABSTRACT: Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SB 223412, hNK-3-CHO binding Ki = 1.4 nM) and 55 (3-NH2, hNK-3-CHO binding Ki = 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 μM. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists.
  03/1999;
• Article: Endothelin and the respiratory system

  Douglas W.P. Hay, Peter J. Henry, Roy G. Goldie
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  ABSTRACT: Pharmacological research involving the endothelin peptides has emphasized their activities in vascular systems, from both physiological and pathophysiological perspectives. However, the endothelins are known also to be synthesized and released from respiratory epithelial cells and to have potent effects in nonvascular components of the respiratory tract. Douglas Hay, Peter Henry and Roy Goldie summarize present understanding of the pharmacology of the endothelins in the respiratory system and assess the potential pathophysiological role in asthma.
  Trends in Pharmacological Sciences 02/1993; · 10.93 Impact Factor