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ABSTRACT: A general and facile one-pot procedure for the synthesis of 2-substituted pyridines from the corresponding pyridine-N-oxides and nucleophiles is presented as a mild alternative to S(N)Ar chemistry. A variety of nucleophiles and heterocyclic-N-oxides participate effectively in this transformation, which uses the phosphonium salt, PyBroP, as a means of substrate activation.
Organic Letters 03/2011; 13(7):1840-3. · 5.86 Impact Factor
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ABSTRACT: A general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from the corresponding pyridine-N-oxides is presented as a mild alternative to S(N)Ar chemistry. A variety of amines and heterocyclic-N-oxides participate effectively in this transformation which uses the phosphonium salt, PyBroP, as a means of substrate activation.
Organic Letters 10/2010; 12(22):5254-7. · 5.86 Impact Factor
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Kevin D Freeman-Cook,
Christopher Autry,
Gary Borzillo,
Deborah Gordon,
Elsa Barbacci-Tobin,
Vincent Bernardo,
David Briere,
Tracey Clark,
Matthew Corbett,
John Jakubczak, [......],
Gary Martinelli,
Matthew Marx,
Kendra Nelson,
Jayvardhan Pandit,
Francis Rajamohan,
Shaughnessy Robinson,
Chakrapani Subramanyam, Liuqing Wei,
Martin Wythes,
Joel Morris
Journal of Medicinal Chemistry 07/2010; · 4.80 Impact Factor
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Kevin D Freeman-Cook,
Christopher Autry,
Gary Borzillo,
Deborah Gordon,
Elsa Barbacci-Tobin,
Vincent Bernardo,
David Briere,
Tracey Clark,
Matthew Corbett,
John Jakubczak, [......],
Gary Martinelli,
Matthew Marx,
Kendra Nelson,
Jayvardhan Pandit,
Francis Rajamohan,
Shaughnessy Robinson,
Chakrapani Subramanyam, Liuqing Wei,
Martin Wythes,
Joel Morris
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ABSTRACT: This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
Journal of Medicinal Chemistry 06/2010; 53(12):4615-22. · 4.80 Impact Factor
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Gayatri Balan,
Jonathan Bauman,
Samit Bhattacharya,
Mayda Castrodad,
David R Healy,
Michael Herr,
Paul Humphries,
Sandra Jennings,
Amit S Kalgutkar,
Brendon Kapinos, [......],
Constantin Neagu,
Robert Oliver,
David W Piotrowski,
David Price,
Hong Qi,
Holly A Simmons,
James Southers, Liuqing Wei,
Yan Zhang,
Vishwas M Paralkar
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ABSTRACT: The design and profile of a series of zwitterionic calcium sensing receptor negative allosteric modulators is described. Evaluation of key analogues using a rat model demonstrate a robust response, significantly improved potency over ronacaleret and have the potential as an oral, anabolic treatment for osteoporosis.
Bioorganic & medicinal chemistry letters 05/2009; 19(12):3328-32. · 2.65 Impact Factor
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Blaise Lippa,
Gonghua Pan,
Matthew Corbett,
Chao Li,
Goss S Kauffman,
Jayvardhan Pandit,
Shaughnessy Robinson, Liuqing Wei,
Ekaterina Kozina,
Eric S Marr,
Gary Borzillo,
Elisabeth Knauth,
Elsa G Barbacci-Tobin,
Patrick Vincent,
Merin Troutman,
Deborah Baker,
Francis Rajamohan,
Shefali Kakar,
Tracey Clark,
Joel Morris
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ABSTRACT: Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
Bioorganic & medicinal chemistry letters 07/2008; 18(11):3359-63. · 2.65 Impact Factor
