917772-60-2Relevant academic research and scientific papers
Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: Conformational constraint to favor a bioactive conformation
Mandal, Mihirbaran,Zhu, Zhaoning,Cumming, Jared N.,Liu, Xiaoxiang,Strickland, Corey,Mazzola, Robert D.,Caldwell, John P.,Leach, Prescott,Grzelak, Michael,Hyde, Lynn,Zhang, Qi,Terracina, Giuseppe,Zhang, Lili,Chen, Xia,Kuvelkar, Reshma,Kennedy, Matthew E.,Favreau, Leonard,Cox, Kathleen,Orth, Peter,Buevich, Alexei,Voigt, Johannes,Wang, Hongwu,Kazakevich, Irina,McKittrick, Brian A.,Greenlee, William,Parker, Eric M.,Stamford, Andrew W.
, p. 9331 - 9345 (2013/01/15)
On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2′ binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2′. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aβ40 in the plasma, CSF, and cortex of rats in a dose-dependent manner.
THIOPHENYL-SUBSTITUTED 2-IMINO-3-METHYL PYRROLO PYRIMIDINONE COMPOUNDS AS BACE-1 INHIBITORS, COMPOSITIONS, AND THEIR USE
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, (2009/12/05)
In its many embodiments, the present invention provides provides certain thiophenyl-substituted 2-imino-3-methyl pyrrolo pyrimidone compounds, including compounds (or tautomers or a pharmaceutically acceptable salts thereof) having the structural Formula (III): wherein R2, R3, R4, R5, R6, R7, R8, and R9 are each selected independently and as defined herein. Pharmaceutical compositions comprising one or more such compounds, and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's Disease, are also disclosed.
ASPARTYL PROTEASE INHIBITORS
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Page/Page column 45; 47, (2008/06/13)
Disclosed are compounds of the formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein j, k, U, W, R, R1, R2, R3, R4, R6, R7 and R7a are as described above in the specification. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula (I) in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.
