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Min Teng,
Jinjiang Zhu, Michael D Johnson,
Ping Chen,
Jill Kornmann,
Enhong Chen,
Alessandra Blasina,
James Register,
Kenna Anderes,
Caroline Rogers,
Yali Deng,
Sacha Ninkovic,
Stephan Grant,
Qiyue Hu,
Karen Lundgren,
Zhengwei Peng,
Robert S Kania
[show abstract]
[hide abstract]
ABSTRACT: The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.
Journal of Medicinal Chemistry 12/2007; 50(22):5253-6. · 5.25 Impact Factor
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Min Teng, Michael D Johnson,
Christine Thomas,
Dan Kiel,
James N Lakis,
Tim Kercher,
Shelley Aytes,
Jarek Kostrowicki,
Dilip Bhumralkar,
Larry Truesdale, [......],
Janos T Kodra,
Anker Steen Jørgensen,
Preben Houlberg Olesen,
Johannes Cornelis de Jong,
Peter Madsen,
Carsten Behrens,
Ingrid Pettersson,
Lotte Bjerre Knudsen,
Jens J Holst,
Jesper Lau
[show abstract]
[hide abstract]
ABSTRACT: Following our previous publication describing the biological profiles, we herein describe the structure-activity relationships of a core set of quinoxalines as the hGLP-1 receptor agonists. The most potent and efficacious compounds are 6,7-dichloroquinoxalines bearing an alkyl sulfonyl group at the C-2 position and a secondary alkyl amino group at the C-3 position. These findings serve as a valuable starting point for the discovery of more drug-like small molecule agonists for the hGLP-1 receptor.
Bioorganic & Medicinal Chemistry Letters 11/2007; 17(19):5472-8. · 2.55 Impact Factor
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Min Teng,
Jinjiang Zhu, Michael D. Johnson,
Ping Chen,
Jill Kornmann,
Enhong Chen,
Alessandra Blasina,
James Register,
Kenna Anderes,
Caroline Rogers,
Yali Deng,
Sacha Ninkovic,
Stephan Grant,
Qiyue Hu,
Karen Lundgren,
Zhengwei Peng,
Robert S. Kania
[show abstract]
[hide abstract]
ABSTRACT: The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.
09/2007;
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Lotte Bjerre Knudsen,
Dan Kiel,
Min Teng,
Carsten Behrens,
Dilip Bhumralkar,
János T Kodra,
Jens J Holst,
Claus B Jeppesen, Michael D Johnson,
Johannes Cornelis de Jong, [......],
Jarek Kostrowicki,
Peter Madsen,
Preben H Olesen,
Jacob S Petersen,
Fritz Poulsen,
Ulla G Sidelmann,
Jeppe Sturis,
Larry Truesdale,
John May,
Jesper Lau
[show abstract]
[hide abstract]
ABSTRACT: The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.
Proceedings of the National Academy of Sciences 02/2007; 104(3):937-42. · 9.68 Impact Factor
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Peter Madsen,
Anthony Ling,
Michael Plewe,
Christian K Sams,
Lotte B Knudsen,
Ulla G Sidelmann,
Lars Ynddal,
Christian L Brand,
Birgitte Andersen,
Douglas Murphy, [......],
John May,
Atsuo Kuki,
Shenghua Shi, Michael D Johnson,
Kimberly Ann Teston,
Jun Feng,
James Lakis,
Kenna Anderes,
Vlad Gregor,
Jesper Lau
[show abstract]
[hide abstract]
ABSTRACT: 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-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 430 pM, K(B) = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K(i) = 14 nM). This compound was orally available in dogs (F(po) = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.
Journal of Medicinal Chemistry 01/2003; 45(26):5755-75. · 5.25 Impact Factor
