Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase

Keith Clinch; Gary B. Evans; Richard F.G. Frohlich; Richard H. Furneaux; Peter M. Kelly; Laurent Legentil; Andrew S. Murkin; Lei Li; Vern L. Schramm; Peter C. Tyler; Anthony D. Woolhouse

doi:10.1021/jm801421q

Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase

Keith Clinch
, Gary B. Evans
, Richard F.G. Frohlich
, Richard H. Furneaux
, Peter M. Kelly
, Laurent Legentil
, Andrew S. Murkin
, Lei Li
, Vern L. Schramm
, Peter C. Tyler
, Anthony D. Woolhouse

Chemistry

Callaghan Innovation
Albert Einstein College of Medicine

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe- ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K _d = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.

Original language	English
Pages (from-to)	1126-1143
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	4
DOIs	https://doi.org/10.1021/jm801421q
State	Published - Feb 26 2009

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Clinch, K., Evans, G. B., Frohlich, R. F. G., Furneaux, R. H., Kelly, P. M., Legentil, L., Murkin, A. S., Li, L., Schramm, V. L., Tyler, P. C., & Woolhouse, A. D. (2009). Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase. Journal of Medicinal Chemistry, 52(4), 1126-1143. https://doi.org/10.1021/jm801421q

@article{37c85be001914ebeb8b09a75b20163f4,

title = "Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase",

abstract = "ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe- ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K d = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.",

author = "Keith Clinch and Evans, \{Gary B.\} and Frohlich, \{Richard F.G.\} and Furneaux, \{Richard H.\} and Kelly, \{Peter M.\} and Laurent Legentil and Murkin, \{Andrew S.\} and Lei Li and Schramm, \{Vern L.\} and Tyler, \{Peter C.\} and Woolhouse, \{Anthony D.\}",

year = "2009",

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doi = "10.1021/jm801421q",

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volume = "52",

pages = "1126--1143",

journal = "Journal of Medicinal Chemistry",

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Clinch, K, Evans, GB, Frohlich, RFG, Furneaux, RH, Kelly, PM, Legentil, L, Murkin, AS, Li, L, Schramm, VL, Tyler, PC & Woolhouse, AD 2009, 'Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase', Journal of Medicinal Chemistry, vol. 52, no. 4, pp. 1126-1143. https://doi.org/10.1021/jm801421q

TY - JOUR

T1 - Third-generation immucillins

T2 - Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase

AU - Clinch, Keith

AU - Evans, Gary B.

AU - Frohlich, Richard F.G.

AU - Furneaux, Richard H.

AU - Kelly, Peter M.

AU - Legentil, Laurent

AU - Murkin, Andrew S.

AU - Li, Lei

AU - Schramm, Vern L.

AU - Tyler, Peter C.

AU - Woolhouse, Anthony D.

PY - 2009/2/26

Y1 - 2009/2/26

N2 - ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe- ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K d = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.

AB - ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe- ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K d = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 4

ER -

Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase

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