- Glucagon antagonists/inverse agonists
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Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof are disclosed. The compounds act to antagonize the action of the glucagon peptide hormone.
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- Optimization of alkylidene hydrazide based human glucagon receptor antagonists. Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1h-indol-4ylmethylene]hydrazide
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Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure - metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, KB = 760 pM) and of the isolated rat receptor (IC50 = 430 pM, KB = 380 pM). Glucagonstimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (Ki = 14 nM). This compound was orally available in dogs (Fpo = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.
- Madsen, Peter,Ling, Anthony,Plewe, Michael,Sams, Christian K.,Knudsen, Lotte B.,Sidelmann, Ulla G.,Ynddal, Lars,Brand, Christian L.,Andersen, Birgitte,Murphy, Douglas,Teng, Min,Truesdale, Larry,Kiel, Dan,May, John,Kuki, Atsuo,Shi, Shenghua,Johnson, Michael D.,Teston, Kimberly Ann,Feng, Jun,Lakis, James,Anderes, Kenna,Gregor, Vlad,Lau, Jesper
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p. 5755 - 5775
(2007/10/03)
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- Discovery of novel, orally active dual NK1/NK2 antagonists
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Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (Ki=0.12 and 0.62 nM, respectively). In functional assays ZD6021 had, at 10-7 M, in human pulmonary artery pKB=8.9 and in human bronchus pKB=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED50=0.5 mg/kg, and NK2 mediated bronchoconstriction, ED50=13 mg/kg.
- Bernstein, Peter R.,Aharony, David,Albert, Jeffrey S.,Andisik, Donald,Barthlow, Herbert G.,Bialecki, Russell,Davenport, Timothy,Dedinas, Robert F.,Dembofsky, Bruce T.,Koether, Gerard,Kosmider, Benedict J.,Kirkland, Karin,Ohnmacht, Cyrus J.,Potts, William,Rumsey, William L.,Shen, Lihong,Shenvi, Ashok,Sherwood, Scott,Stollman, David,Russell, Keith
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p. 2769 - 2773
(2007/10/03)
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- 13C NMR investigation of electronic interactions in 5-substituted 1-naphthonitriles
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Carbon-13 NMR chemical shifts of 5-Z-substituted 1-naphthonitriles (1; Z = H, F, Cl, Br, NH2, NMe2, CN, NO2, OMe, CHO, CO2Me) in deuteriochloroform and in neat trifluoroacetic acid (TFA) are reported. The CN carbon shifts are found to correlate well with the dual substituent parameters (DSPs). Negative values of the transmission coefficients in the DSP correlation give evidence of a reverse substituent electronic effect, which is associated with variations in π polarization of the CN multiple bond, due primarily to differences in the through-space field effects of the various Z. The effect diminishes for 1 in neat TFA because of the greater contribution of dipolar ArC+=N- to the resonance hybrid. Deviations of the aromatic carbon shifts from substituent chemical shift additivities are small, yet show distinct patterns for many of the carbon resonances. The deviations of the C-1 - CN ipso carbon shifts of 1 in neutral solvents and in TFA correlate roughly with the DSPs. They are attributable to changes in charge density at C-1 that arise as a consequence of substituent-induced changes in the polarity of the CN bond. The greater than expected shielding that is observed for the C-6 and C-8 resonances accords with reduced electron withdrawal by +R substituents and increased mesomeric activity by electron-donating groups, Z, in response to the CN-induced charge depletion within the adjacent aromatic ring. From the location of data for 5-methoxy-1-naphthonitrile (1; Z = OMe) in the chemical shift correlations of 1 in neat TFA, one can conclude that the methoxy group of this compound, unlike that of 1-methoxynaphthalene itself, is not significantly hydrogen-bonded by TFA.
- Schuster, Ingeborg I.
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p. 301 - 310
(2007/10/03)
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