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Jeffrey T Mihalic, Pingchen Fan,
Xiaoqi Chen,
Xi Chen,
Ying Fu,
Alykhan Motani,
Lingming Liang,
Michelle Lindstrom,
Liang Tang,
Jin-Long Chen,
Juan Jaen,
Kang Dai,
Leping Li
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ABSTRACT: An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.
Bioorganic & medicinal chemistry letters 04/2012; 22(11):3781-5. · 2.65 Impact Factor
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Jeffrey T Mihalic,
Xiaoqi Chen, Pingchen Fan,
Xi Chen,
Ying Fu,
Lingming Liang,
Michael Reed,
Liang Tang,
Jin-Long Chen,
Juan Jaen,
Leping Li,
Kang Dai
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ABSTRACT: A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model.
Bioorganic & medicinal chemistry letters 12/2011; 21(23):7001-5. · 2.65 Impact Factor
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Xiaoqi Chen,
Jeff Mihalic, Pingchen Fan,
Lingming Liang,
Michelle Lindstrom,
Sylvia Wong,
Qiuping Ye,
Ying Fu,
Juan Jaen,
Jin-Long Chen,
Kang Dai,
Leping Li
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ABSTRACT: A series of spiropiperidine carbazoles were synthesized and evaluated as MCHR2 antagonists using a FLIPR assay. The pharmacokinetic properties of selected compounds have also been studied. This effort led to the discovery of potent and specific MCHR2 antagonists. Compound 38 demonstrated good pharmacokinetic properties across rat, beagle dog and rhesus monkey and had a favorable selectivity profile against a number of other receptors. These MCHR2 antagonists are considered appropriate tool compounds for study of the function of MCHR2 in vivo.
Bioorganic & medicinal chemistry letters 11/2011; 22(1):363-6. · 2.65 Impact Factor
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Xuelei Yan,
Zhulun Wang,
Athena Sudom,
Mario Cardozo,
Michael DeGraffenreid,
Yongmei Di, Pingchen Fan,
Xiao He,
Juan C Jaen,
Marc Labelle, [......],
Ji Ma,
Dustin McMinn,
Shichang Miao,
Daqing Sun,
Liang Tang,
Hua Tu,
Stefania Ursu,
Nigel Walker,
Qiuping Ye,
Jay P Powers
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ABSTRACT: In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Bioorganic & medicinal chemistry letters 09/2010; 20(23):7071-5. · 2.65 Impact Factor
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Alykhan Motani,
Zhulun Wang,
Marion Conn,
Karen Siegler,
Ying Zhang,
Qingxiang Liu,
Sheree Johnstone,
Haoda Xu,
Steve Thibault,
Yingcai Wang, Pingchen Fan,
Richard Connors,
Hoa Le,
Guifen Xu,
Nigel Walker,
Bei Shan,
Peter Coward
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ABSTRACT: Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (K(i) = 8.3 nm) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin. Analysis of the RBP4-A1120 co-crystal structure reveals that A1120 induces critical conformational changes at the RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4 and retinol levels but, unexpectedly, does not improve insulin sensitivity. In addition, we show that Rpb4(-/-) mice display normal insulin sensitivity and are not protected from high fat diet-induced insulin resistance. We conclude that lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore, RBP4 lowering may not be an effective strategy for treating diabetes.
Journal of Biological Chemistry 02/2009; 284(12):7673-80. · 4.77 Impact Factor
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Denise Andersen,
Thomas Storz,
Pingli Liu,
Xin Wang,
Leping Li, Pingchen Fan,
Xiaoqi Chen,
Alan Allgeier,
Alain Burgos,
Jason Tedrow,
Jean Baum,
Ying Chen,
Rich Crockett,
Liang Huang,
Rashid Syed,
Robert D Larsen,
Mike Martinelli
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ABSTRACT: Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.
The Journal of Organic Chemistry 01/2008; 72(25):9648-55. · 4.45 Impact Factor
