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Douglas E Wilkinson,
Bert E Thomas,
David C Limburg,
Agnes Holmes,
Hansjorg Sauer,
Douglas T Ross,
Raj Soni,
Yi Chen,
Hong Guo, Pamela Howorth,
Heather Valentine,
Dawn Spicer,
Mike Fuller,
Joseph P Steiner,
Gregory S Hamilton,
Yong-Qian Wu
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ABSTRACT: Nonimmunosuppressant ligands, exemplified by GPI 1046 (1), for the peptidyl-prolyl isomerase FKBP12 have been found to unexpectedly possess powerful neuroprotective and neuroregenerative effects in vitro and in vivo. We have extensively explored the therapeutic utility of FKBP12 ligands based on analogues of proline and pipecolic acid. As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing aza-proline and aza-pipecolic acid analogues. Details of the synthetic studies, together with biological activity will be presented.
Bioorganic & Medicinal Chemistry 12/2003; 11(22):4815-25. · 2.92 Impact Factor
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Gregory S Hamilton,
Yong-Qian Wu,
David C Limburg,
Douglas E Wilkinson,
Mark J Vaal,
Jia-He Li,
Christine Thomas,
Wei Huang,
Hansjorg Sauer,
Douglas T Ross,
Raj Soni,
Yi Chen,
Hongshi Guo, Pamela Howorth,
Heather Valentine,
Shi Liang,
Dawn Spicer,
Mike Fuller,
Joseph P Steiner
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ABSTRACT: The recent discovery that small molecule ligands for the peptidyl-prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.
Journal of Medicinal Chemistry 09/2002; 45(16):3549-57. · 5.25 Impact Factor
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Chi Choi,
Jia-He Li,
Mark Vaal,
Christine Thomas,
David Limburg,
Yong-Qian Wu,
Yi Chen,
Raj Soni,
Chad Scott,
Douglas T Ross,
Hong Guo, Pamela Howorth,
Heather Valentine,
Shi Liang,
Dawn Spicer,
Mike Fuller,
Joseph Steiner,
Gregory S Hamilton
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ABSTRACT: Using simple, inexpensive equipment, we have used solution-phase parallel synthesis to rapidly prepare hundreds of sulfonamide- and urea-containing FKBP inhibitors, resulting in rapid identification of extremely potent compounds in these series.
Bioorganic & Medicinal Chemistry Letters 06/2002; 12(10):1421-8. · 2.55 Impact Factor
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Ling Wei,
Yon- Qian Wu,
Douglas E Wilkinson,
Yi Chen,
Raj Soni,
Chad Scott,
Douglas T Ross,
Hong Guo, Pamela Howorth,
Heather Valentine,
Shi Liang,
Dawn Spicer,
Mike Fuller,
Joseph Steiner,
Gregory S Hamilton
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ABSTRACT: In parallel with our work on solution-phase parallel synthesis of ligands for the rotamase enzyme FKBP12, we herein report a methodology for the solid-phase synthesis of two classes of inhibitor, N-sulfonyl and N-carbamoylprolyl and pipecolyl amides along with their in vitro/in vivo biological results.
Bioorganic & Medicinal Chemistry Letters 06/2002; 12(10):1429-33. · 2.55 Impact Factor
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Joseph P. Steiner,
Gregory S. Hamilton,
Douglas T. Ross,
Heather L. Valentine,
Hongzhi Guo,
Maureen A. Connolly,
Shi Liang,
Cynthia Ramsey,
Jia-He J. Li,
Wei Huang, Pamela Howorth,
Rajat Soni,
Michael Fuller,
Hans Sauer,
Alison C. Nowotnik,
Peter D. Suzdak
Proceedings of the National Academy of Sciences 03/1997; 94(5):2019-2024. · 9.68 Impact Factor
