- Discovery of triazolopyrimidine-based PDE8B inhibitors: Exceptionally ligand-efficient and lipophilic ligand-efficient compounds for the treatment of diabetes
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PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8B inhibition. Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE). These triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.
- Deninno, Michael P.,Wright, Stephen W.,Etienne, John B.,Olson, Thanh V.,Rocke, Benjamin N.,Corbett, Jeffrey W.,Kung, Daniel W.,Dirico, Kenneth J.,Andrews, Kim M.,Millham, Michele L.,Parker, Janice C.,Esler, William,Van Volkenburg, Maria,Boyer, David D.,Houseknecht, Karen L.,Doran, Shawn D.
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scheme or table
p. 5721 - 5726
(2012/09/22)
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- SUBSTITUTED TRIAZOLOPYRIMIDINES AS PDE8 INHIBITORS
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Compounds of Formula (I): wherein R1 , R2, R3, R4, and R5 are as defined herein, are disclosed.
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Page/Page column 35-36
(2011/06/16)
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- PYRIMIDINE DERIVATIVES FOR THE TREATMENT OP GABA B MEDIATED NERVOUS SYSTEM DISORDERS
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The invention relates to novel heterocyclic compounds of the formula (I) in free base form or in acid addition salt form, in which R1, R2, R3, R4 and A are as defined in the specification, to their preparation, to their use as medicaments for the treatment of certain nervous system disorders and to medicaments comprising them.
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Page/Page column 26-27
(2010/11/25)
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