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ABSTRACT: 3-Phenylpyrazolo[4,3-b]pyridines were synthesized via a cyclization of 4-amino-3-phenylpyrazoles 11-13 with ethyl acetoacetate. These compounds were found to be potent CRF(1) antagonists. The 2-alkylpyrazolo[4,3-b]pyridines were more polar but less active than the corresponding 1-alkyl-isomers.
Bioorganic & Medicinal Chemistry Letters 11/2003; 13(19):3367-70. · 2.55 Impact Factor
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ABSTRACT: 1-Methyl-3-phenylpyrazolo[4,3-b]pyridines were synthesized via a cyclization reaction of 1-methyl-4-amino-3-phenylpyrazoles 8 with ethyl acetoacetate. Optimization of this series of compounds resulted in CRF(1) antagonists with subnanomolar binding affinity. Compounds bearing a polar group such as methoxy or hydroxy were also found to be very active.
Bioorganic & Medicinal Chemistry Letters 11/2003; 13(19):3371-4. · 2.55 Impact Factor
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ABSTRACT: A series of 4-substituted 8-aryl-2-methylquinolines 4 was designed and synthesized as highly potent antagonists for the human CRF(1) receptor. This series of compounds displayed parallel SAR to other bicyclic systems such as pyrazolo[1,5-a]pyrimidines, with several compounds possessing low nanomolar binding affinity. In addition to the high potency, the basicity of this 4-aminoquinoline core may offer CRF(1) antagonists with lower lipophilicity.
Bioorganic & Medicinal Chemistry Letters 11/2003; 13(19):3375-9. · 2.55 Impact Factor
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Yun-Fei Zhu, Keith Wilcoxen,
Timothy Gross,
Patrick Connors,
Nathalie Strack,
Raymond Gross,
Charles Q Huang,
James R McCarthy,
Qiu Xie,
Nicholas Ling,
Chen Chen
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ABSTRACT: A series of 1-benzoyl isoquinolines, based on compound 1, was synthesized and evaluated for their ability to displace IGF-I from its complex with IGF-binding protein-3. Successful modifications of 1 included the replacement of the 3,4-dihydroxybenzoyl group with a substituted benzyl group. These alternations culminated in the discovery of compounds such as 7o which had excellent in vitro potency (K(i)=9.4 nM) but with one less of the labile catechol functionality of 1.
Bioorganic & Medicinal Chemistry Letters 07/2003; 13(11):1927-30. · 2.55 Impact Factor
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Yun-Fei Zhu,
Xiao-Chuan Wang,
Patrick Connors, Keith Wilcoxen,
Yinghong Gao,
Raymond Gross,
Nathalie Strack,
Timothy Gross,
James R McCarthy,
Qiu Xie,
Nicholas Ling,
Chen Chen
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ABSTRACT: 4-benzylquinolines 5, based on a series of isoquinolines 1, were prepared and tested as inhibitors of the IGF/IGFBP-3 complex based on their ability to displace IGF-I from its binding to IGF-binding protein-3. SAR studies on the 6,7-dihydroxy moiety of the quinoline 5a showed that the catecol moiety could be replaced with other functional groups. Computational modeling of the 5a/mini-IGFBP-5 complex revealed the possible binding site of 5a on IGFBP-5.
Bioorganic & Medicinal Chemistry Letters 07/2003; 13(11):1931-4. · 2.55 Impact Factor
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ABSTRACT: Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2-a]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM (K(i)) binding affinity to human GnRH receptor.
Bioorganic & Medicinal Chemistry Letters 03/2002; 12(3):399-402. · 2.55 Impact Factor
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Yun-Fei Zhu, Keith Wilcoxen,
John Saunders,
Zhiqiang Guo,
Yinghong Gao,
Patrick J Connors,
Timothy D Gross,
Fabio C Tucci,
R Scott Struthers,
Greg J Reinhart,
Qiu Xie,
Chen Chen
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ABSTRACT: In the process of developing GnRH receptor antagonists, a novel base-catalyzed cyclization of compounds 5a-b was discovered, which led to the formation of the 2-aryl pyrrolo[1,2-a]pyrimid-7-one core structures 6a-b. These intermediates were further modified at positions 1, 2, 4 and 6 to afford a series of potent GnRH antagonists with low nanomolar K(i) values.
Bioorganic & Medicinal Chemistry Letters 03/2002; 12(3):403-6. · 2.55 Impact Factor
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ABSTRACT: The palladium-catalyzed cross-coupling reactions of (E)- or (Z)-1-fluorovinylstannanes with aryl iodides and vinyl iodides provide good yields of stereoisomerically pure substituted fluoroolefins with retention of the double bond geometry. The reaction takes place with copper(I) iodide present as a cocatalyst at ambient temperature or in refluxing tetrahydrofuran and is tolerant of a variety of functional groups. Highly functionalized and stereoisomerically pure monofluorovinyl ketones also were obtained under mild conditions by the coupling of 1-fluorovinylstannanes with acid chlorides. (1)H-{(19)F} NOE NMR experiments unequivocally established the stereochemistry of the coupling products E-14 and Z-14.
The Journal of Organic Chemistry 06/1999; 64(10):3476-3482. · 4.45 Impact Factor
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Tetrahedron Letters 39(45):8229-8232. · 2.68 Impact Factor
