Henry M Sarau

Publications (43)162.16 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: Tyrosine urea muscarinic acetylcholine receptor antagonists: Achiral quaternary ammonium groups.

  Qi Jin, Roderick S Davis, Ann M Bullion, Jian Jin, Yonghui Wang, Katherine L Widdowson, Michael R Palovich, James J Foley, Dulcie B Schmidt, Peter T Buckley, Edward F Webb, Michael Salmon, Kristen E Belmonte, Henry M Sarau, Jakob Busch-Petersen
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  ABSTRACT: Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction.
  Bioorganic & medicinal chemistry letters 10/2012; · 2.65 Impact Factor
• Article: Design, synthesis and structure-activity relationship of N-substituted tropane muscarinic acetylcholine receptor antagonists.

  Dramane I Lainé, Hongxing Yan, Haibo Xie, Roderick S Davis, Jeremy Dufour, Katherine L Widdowson, Michael R Palovich, Zehong Wan, James J Foley, Dulcie B Schmidt, [......], Miriam Burman, Alicia M Bacon, Edward F Webb, Mark A Luttmann, Michael Salmon, Henry M Sarau, Sandra T Umbrecht, Philip S Landis, Brian J Peck, Jakob Busch-Petersen
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  ABSTRACT: A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
  Bioorganic & medicinal chemistry letters 02/2012; 22(9):3366-9. · 2.65 Impact Factor
• Article: Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD.

  Zehong Wan, Dramane I Laine, Hongxing Yan, Chongjie Zhu, Katherine L Widdowson, Peter T Buckley, Miriam Burman, James J Foley, Henry M Sarau, Dulcie B Schmidt, Edward F Webb, Kristen E Belmonte, Michael Palovich
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  ABSTRACT: Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery.
  Bioorganic & medicinal chemistry letters 09/2009; 19(16):4560-2. · 2.65 Impact Factor
• Article: Design, synthesis, and structure-activity relationship of tropane muscarinic acetylcholine receptor antagonists.

  Dramane I Lainé, Zehong Wan, Hongxing Yan, Chongjie Zhu, Haibo Xie, Wei Fu, Jakob Busch-Petersen, Christopher Neipp, Roderick Davis, Katherine L Widdowson, Frank E Blaney, James Foley, Alicia M Bacon, Edward F Webb, Mark A Luttmann, Miriam Burman, Henry M Sarau, Michael Salmon, Michael R Palovich, Kristen Belmonte
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  ABSTRACT: Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.
  Journal of Medicinal Chemistry 08/2009; 52(16):5241-52. · 4.80 Impact Factor
• Article: M3 muscarinic acetylcholine receptor antagonists: SAR and optimization of bi-aryl amines.

  Brian Budzik, Yonghui Wang, Dongchuan Shi, Feng Wang, Haibo Xie, Zehong Wan, Chongye Zhu, James J Foley, Parvathi Nuthulaganti, Lorena A Kallal, Henry M Sarau, Dwight M Morrow, Michael L Moore, Ralph A Rivero, Michael Palovich, Michael Salmon, Kristen E Belmonte, Dramane I Laine, Jian Jin
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  ABSTRACT: Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.
  Bioorganic & medicinal chemistry letters 03/2009; 19(6):1686-90. · 2.65 Impact Factor
• Article: Camphor sulfonamide derivatives as novel, potent and selective CXCR3 antagonists.

  Yonghui Wang, Jakob Busch-Petersen, Feng Wang, Terence J Kiesow, Todd L Graybill, Jian Jin, Zheng Yang, James J Foley, Gerald E Hunsberger, Dulcie B Schmidt, Henry M Sarau, Elizabeth A Capper-Spudich, Zining Wu, Laura S Fisher, Michael S McQueney, Ralph A Rivero, Katherine L Widdowson
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  ABSTRACT: A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described.
  Bioorganic & medicinal chemistry letters 12/2008; 19(1):114-8. · 2.65 Impact Factor
• Article: Muscarinic acetylcholine receptor antagonists: SAR and optimization of tyrosine ureas.

  Jian Jin, Yonghui Wang, Dongchuan Shi, Feng Wang, Wei Fu, Roderick S Davis, Qi Jin, James J Foley, Henry M Sarau, Dwight M Morrow, Michael L Moore, Ralph A Rivero, Michael Palovich, Michael Salmon, Kristen E Belmonte, Jakob Busch-Petersen
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  ABSTRACT: SAR exploration of multiple regions of a tyrosine urea template led to the identification of very potent muscarinic acetylcholine receptor antagonists such as 10b with good subtype selectivity for M(3) over M(1). The structure-activity relationships (SAR) and optimization of the tyrosine urea series are described.
  Bioorganic & medicinal chemistry letters 10/2008; 18(20):5481-6. · 2.65 Impact Factor
• Article: Discovery of novel and long acting muscarinic acetylcholine receptor antagonists.

  Jian Jin, Yonghui Wang, Dongchuan Shi, Feng Wang, Roderick S Davis, Qi Jin, Wei Fu, James J Foley, Edward F Webb, Chris J Dehaas, [......], Henry M Sarau, Dwight M Morrow, Parvathi Rao, Lorena A Kallal, Michael L Moore, Ralph A Rivero, Michael Palovich, Michael Salmon, Kristen E Belmonte, Jakob Busch-Petersen
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  ABSTRACT: High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
  Journal of Medicinal Chemistry 09/2008; 51(16):4866-9. · 4.80 Impact Factor
• Article: Urotensin-II receptor antagonists: synthesis and SAR of N-cyclic azaalkyl benzamides.

  Jian Jin, Ming An, Anthony Sapienza, Nambi Aiyar, Diane Naselsky, Henry M Sarau, James J Foley, Kevin L Salyers, Steven D Knight, Richard M Keenan, Ralph A Rivero, Dashyant Dhanak, Stephen A Douglas
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  ABSTRACT: SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human urotensin-II receptor antagonists such as 1a with a K(i) of 4 nM. The synthesis and structure-activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.
  Bioorganic & medicinal chemistry letters 08/2008; 18(14):3950-4. · 2.65 Impact Factor
• Article: 3-Arylamino-2H-1,2,4-benzothiadiazin-5-ol 1,1-dioxides as novel and selective CXCR2 antagonists.

  Yonghui Wang, Jakob Busch-Petersen, Feng Wang, Lanping Ma, Wei Fu, Jeffrey K Kerns, Jian Jin, Michael R Palovich, Jing-Kang Shen, Miriam Burman, James J Foley, Dulcie B Schmidt, Gerald E Hunsberger, Henry M Sarau, Katherine L Widdowson
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  ABSTRACT: A series of 3-arylamino-2H-1,2,4-benzothiadiazin-5-ol 1,1-dioxides were prepared and shown to be novel and selective antagonists of the CXCR2 receptor. Synthesis, structure and activity relationships, selectivity, and some developability properties are described.
  Bioorganic & Medicinal Chemistry Letters 08/2007; 17(14):3864-7. · 2.55 Impact Factor
• Article: Oxazolidinones as novel human CCR8 antagonists.

  Jian Jin, Yonghui Wang, Feng Wang, Jeffery K Kerns, Victoria M Vinader, Ashley P Hancock, Matthew J Lindon, Graeme I Stevenson, Dwight M Morrow, Parvathi Rao, [......], David P Andrew, Henry M Sarau, James J Foley, Anthony J Jurewicz, James A Fornwald, Andy J Harker, Michael L Moore, Ralph A Rivero, Kristen E Belmonte, Helen E Connor
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  ABSTRACT: High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.
  Bioorganic & Medicinal Chemistry Letters 04/2007; 17(6):1722-5. · 2.55 Impact Factor
• Article: Comparison of N,N'-diarylsquaramides and N,N'-diarylureas as antagonists of the CXCR2 chemokine receptor.

  Brent W McCleland, Roderick S Davis, Michael R Palovich, Katherine L Widdowson, Michelle L Werner, Miriam Burman, James J Foley, Dulcie B Schmidt, Henry M Sarau, Martin Rogers, Kevin L Salyers, Peter D Gorycki, Theresa J Roethke, Gary J Stelman, Leonard M Azzarano, Keith W Ward, Jakob Busch-Petersen
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  ABSTRACT: N,N'-diarylsquaramides were prepared and evaluated as antagonists of CXCR2. The compounds were found to be potent and selective antagonists of CXCR2. Significant differences in SAR was observed relative to the previously described N,N'-diarylurea series. As was the case in the N,N'-diarylurea series, placing sulfonamide substituent adjacent to the acidic phenol significantly reduced the clearance in rat pharmacokinetic studies.
  Bioorganic & Medicinal Chemistry Letters 04/2007; 17(6):1713-7. · 2.55 Impact Factor
• Article: A novel flow cytometric assay of human whole blood neutrophil and monocyte CD11b levels: upregulation by chemokines is related to receptor expression, comparison with neutrophil shape change, and effects of a chemokine receptor (CXCR2) antagonist.

  Grant C Nicholson, Rachel C Tennant, Donald C Carpenter, Henry M Sarau, Onn Min Kon, Peter J Barnes, Michael Salmon, Rupert S Vessey, Ruth Tal-Singer, Trevor T Hansel
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  ABSTRACT: Smokers who develop chronic obstructive pulmonary disease (COPD) have amplified inflammation within their lungs, involving selective tissue accumulation of neutrophils, macrophages and CD8+ T cells. CD11b (Mac-1, alphaMbeta(2)-integrin) is both a complement receptor (CR3) and a cell adhesion molecule present on the surface of peripheral blood leukocytes, and undergoes rapid surface upregulation from preformed cytoplasmic stores on activation. Cellular activation can also trigger chemotaxis and shape change, the activation itself being caused by the binding of chemokines to cell surface receptors. We developed a method of whole blood flow cytometry to measure neutrophil and monocyte CD11b upregulation on CD16+ and CD14+ cells, employing staining with the nuclear dye LDS-751 immediately before flow cytometry. In addition we assessed neutrophil shape change by modified gated autofluorescence with forward scatter (GAFS), this being correlated with chemotactic responses. In smokers with COPD there was a lower maximal shape change for neutrophils in response to CXCL8 (IL-8) in comparison to healthy smokers (p=0.025), and a trend for lower expression of CD11b and shape change in response to CXCL1 (GRO-alpha). Neutrophils were found to predominantly express chemokine receptors CXCR1 and CXCR2 and respond to CXCL8 with CD11b upregulation, while monocytes express more CCR2 and upregulate CD11b preferentially to CCL2 (MCP-1). A CXCR2 antagonist (SB-656933) was found to inhibit neutrophil CD11b upregulation (IC50=260.7nM) and shape change (IC50=310.5nM) in COPD patients. Neutrophils and monocytes participate in inflammatory processes in a range of diseases. These whole blood assays can be employed to monitor activity in disease and perform in vitro and ex vivo assessment of chemokine receptor (CXCR) antagonists.
  Pulmonary Pharmacology &amp Therapeutics 02/2007; 20(1):52-9. · 2.80 Impact Factor
• Chapter: IL-8 receptor antagonist: basic research and clinical utility

  John R. White, Henry M. Sarau
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  ABSTRACT: Inflammatory cells are thought to be instrumental in the pathophysiology of diseases and the control of their recruitment and activation appears to be an attractive strategy for therapeutic intervention. Chemokines are a family of small molecular weight (7–15 kDa) proteins that in conjunction with adhesion molecules play a crucial role in leukocyte recruitment, cellular activation and proliferation at sites of inflammation. Chemokines are produced by a variety of cell types, including leukocytic and non-leukocytic cells, usually in response to antigens, irritants and other cytokines. Interleukin-8 (CXCL8) was the first member to be identified of this new family of proinflammatory chemokines that now constitute over 45 members. Chemokines produce their biological effects by interacting with greater than 18 G protein coupled cell surface receptors. A few chemokines bind selectively to a single receptor but other chemokines bind to more than one receptor [1, 2]. CXCL8 belongs to a subgroup of chemokines known as ELR+ chemokines because of the Glu4-Leu5-Arg6 amino acid sequence between positions 4 and 6. Other members of this group include CXCL1, 2, 3, 5, 6, and 7. A diverse variety of biological effects are attributed to CXCL8 and related ELR+ chemokines, including several involving inflammatory cell activation and chemotaxis, production of reactive oxygen species, increased expression of the integrin CD11b-CD18, enhancement of cell adhesion to endothelial cells, promotion of angiogenesis, modulation of histamine and lipid mediator release as well as azurophil granule release [3].
  12/2006: pages 89-102;
• Article: N,N'-Diarylcyanoguanidines as antagonists of the CXCR2 and CXCR1 chemokine receptors.

  Hong Nie, Katherine L Widdowson, Michael R Palovich, Wei Fu, John D Elliott, Deborah L Bryan, Miriam Burman, Dulcie B Schmidt, James J Foley, Henry M Sarau, Jakob Busch-Petersen
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  ABSTRACT: A series of N-(2-hydroxy-3-sulfonamidobenzene)-N'-arylcyanoguanidines was prepared. In general, these compounds proved to be potent antagonists of CXCR2 while the selectivity versus CXCR1 ranged from non-selective to >200-fold.
  Bioorganic & Medicinal Chemistry Letters 12/2006; 16(21):5513-6. · 2.55 Impact Factor
• Article: The peptidic urotensin-II receptor ligand GSK248451 possesses less intrinsic activity than the low-efficacy partial agonists SB-710411 and urantide in native mammalian tissues and recombinant cell systems.

  David J Behm, Gerald Stankus, Christopher P A Doe, Robert N Willette, Henry M Sarau, James J Foley, Dulcie B Schmidt, Parvathi Nuthulaganti, James A Fornwald, Robert S Ames, David G Lambert, Girolamo Calo, Valeria Camarda, Nambi V Aiyar, Stephen A Douglas
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  ABSTRACT: Several peptidic urotensin-II (UT) receptor antagonists exert 'paradoxical' agonist activity in recombinant cell- and tissue-based bioassay systems, likely the result of differential urotensin-II receptor (UT receptor) signal transduction/coupling efficiency between assays. The present study has examined this phenomenon in mammalian arteries and recombinant UT-HEK (human embryonic kidney) cells.BacMam-mediated recombinant UT receptor upregulation in HEK cells augmented agonist activity for all four peptidic UT ligands studied. The nominal rank order of relative intrinsic efficacy was U-II>urantide ([Pen(5)-DTrp(7)-Orn(8)]hU-II(4-11))>SB-710411 (Cpa-c[DCys-Pal-DTrp-Lys-Val-Cys]-Cpa-amide)>GSK248451 (Cin-c[DCys-Pal-DTrp-Orn-Val-Cys]-His-amide) (the relative coupling efficiency of recombinant HEK cells was cat>human>rat UT receptor). The present study further demonstrated that the use of high signal transduction/coupling efficiency isolated blood vessel assays (primate>cat arteries) is required in order to characterize UT receptor antagonism thoroughly. This cannot be attained simply by using the rat isolated aorta, an artery with low signal transduction/coupling efficiency in which low-efficacy agonists appear to function as antagonists. In contrast to the 'low-efficacy agonists' urantide and SB-710411, GSK248451 functioned as a potent UT receptor antagonist in all native isolated tissues studied (UT receptor selectivity was confirmed in the rat aorta). Further, GSK248451 exhibited an extremely low level of relative intrinsic activity in recombinant HEK cells (4-5-fold less than seen with urantide). Since GSK248451 (1 mg kg(-1), i.v.) blocked the systemic pressor actions of exogenous U-II in the anaesthetized cat, it represents a suitable peptidic tool antagonist for delineating the role of U-II in the aetiology of mammalian cardiometabolic diseases.
  British Journal of Pharmacology 05/2006; 148(2):173-90. · 4.41 Impact Factor
• Article: Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375.

  Stephen A Douglas, David J Behm, Nambi V Aiyar, Diane Naselsky, Jyoti Disa, David P Brooks, Eliot H Ohlstein, John G Gleason, Henry M Sarau, James J Foley, [......], Katherine Widdowson, Graham Riley, Jian Jin, Timothy F Gallagher, Stanley J Schmidt, Lance Ridgers, Lisa T Christmann, Richard M Keenan, Steven D Knight, Dashyant Dhanak
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  ABSTRACT: 1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 4.6+/-1.4 to 17.6+/-5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (K(app) approximately 20 nM). 5. SB-706375 was a selective U-II antagonist with >/=100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals.
  British Journal of Pharmacology 08/2005; 145(5):620-35. · 4.41 Impact Factor
• Article: Aminoalkoxybenzyl pyrrolidines as novel human urotensin-II receptor antagonists.

  Jian Jin, Dashyant Dhanak, Steven D Knight, Katherine Widdowson, Nambi Aiyar, Diane Naselsky, Henry M Sarau, James J Foley, Dulcie B Schmidt, Carl D Bennett, Bing Wang, Gregory L Warren, Michael L Moore, Richard M Keenan, Ralph A Rivero, Stephen A Douglas
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  ABSTRACT: High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described.
  Bioorganic & Medicinal Chemistry Letters 08/2005; 15(13):3229-32. · 2.55 Impact Factor
• Article: Cloning and pharmacological characterization of the cat urotensin-II receptor (UT).

  Nambi Aiyar, Douglas G Johns, Zhaohui Ao, Jyoti Disa, David J Behm, James J Foley, Peter T Buckley, Henry M Sarau, Harjeet K van-der-Keyl, Nabil A Elshourbagy, Stephen A Douglas
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  ABSTRACT: Urotensin-II (U-II), acting through its G-protein-coupled receptor, UT, is a possible contributor to hypertension. Variable functional responses to U-II, both within and between species studied to date, complicate the characterization of UT antagonists. In the cat, however, U-II causes systemic hypertension and constricts arterial segments isolated from several vascular beds. The purpose of this study was to clone and pharmacologically characterize cat recombinant UT to determine whether this system represents a model for characterizing UT antagonists. Cloned cat UT displayed 74% identity to primate UT, and 77% identity to rodent UT. [(125)I] hU-II bound in a saturable manner to a single site on recombinant cat UT with high affinity (K(D) 288+/-13pM) and high density (B(max) 747+/-66fmol/mg protein). U-II isopeptides displayed equipotent, high affinity binding to cat UT (K(i) 1.8-5.3nM). Cat UT was coupled to intracellular [Ca(2+)] release (EC(50) 0.6+/-0.2nM) and total inositol phosphate (IP) formation (EC(50) 0.4+/-0.1nM). Protein kinase C activation desensitized cat, but not human, UT-mediated IP formation. UT mRNA expression was detected in cat blood vessels, trachea, lung, and kidney, where the medulla (K(D) 815+/-34) and cortex and (K(D) 316+/-39pM) displayed high affinity binding for human U-II (hU-II). The cat urotensin-II receptor represents a suitable in vitro model to examine the role of the U-II/UT system in the etiology of hypertension, assisting in the evaluation of the UT antagonists to help treat cardiovascular disease.
  Biochemical Pharmacology 05/2005; 69(7):1069-79. · 4.70 Impact Factor