Publications by authors named "Jerry W Cubbage"

5 Publications

  • Page 1 of 1

Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).

J Med Chem 2010 Mar;53(6):2656-60

Pfizer Global Research and Development, Chesterfield Parkway West, St Louis, Missouri 63017, USA.

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
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http://dx.doi.org/10.1021/jm901781qDOI Listing
March 2010

Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one.

Bioorg Med Chem Lett 2009 Sep 10;19(17):5209-13. Epub 2009 Jul 10.

Pfizer Global Research and Development, Chesterfield Parkway West, St. Louis, MO 63017, USA.

We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
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http://dx.doi.org/10.1016/j.bmcl.2009.07.019DOI Listing
September 2009

Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.

Bioorg Med Chem Lett 2009 Aug 6;19(15):4088-91. Epub 2009 Jun 6.

Department of Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.

A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
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http://dx.doi.org/10.1016/j.bmcl.2009.06.012DOI Listing
August 2009

Investigation of aminopyridiopyrazinones as PDE5 inhibitors: Evaluation of modifications to the central ring system.

Bioorg Med Chem Lett 2009 Aug 6;19(15):4092-6. Epub 2009 Jun 6.

Pfizer Global Research and Development, Chesterfield Parkway West, St. Louis, MO 63017, USA.

Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.
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http://dx.doi.org/10.1016/j.bmcl.2009.06.004DOI Listing
August 2009

A catch-and-release strategy for the combinatorial synthesis of 4-acylamino-1,3-thiazoles as potential CDK5 inhibitors.

Bioorg Med Chem Lett 2003 Oct;13(20):3491-5

Medicinal Chemistry Research, Pharmacia Corporation, 333 Portage St., Kalamazoo, MI 49007, USA.

Two-dimensional libraries of 4-acylamino-1,3-thiazoles 9 were prepared via Curtius rearrangement of 1,3-thiazole-4-carbonyl azides 6, trapping of the intermediate isocyanates with oxime resin, and thermal regeneration of the isocyanates from the washed resin in the presence of nucleophiles. Several compounds proved to be selective inhibitors of CDK5/p25 versus the closely homologous CDK2/cyclin A enzyme, with the best analogue (43) possessing over 100-fold selectivity.
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http://dx.doi.org/10.1016/s0960-894x(03)00726-1DOI Listing
October 2003