- Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates
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We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2′-S2″ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aβ in nonrodent preclinical species.
- Mandal, Mihirbaran,Wu, Yusheng,Misiaszek, Jeffrey,Li, Guoqing,Buevich, Alexei,Caldwell, John P.,Liu, Xiaoxiang,Mazzola, Robert D.,Orth, Peter,Strickland, Corey,Voigt, Johannes,Wang, Hongwu,Zhu, Zhaoning,Chen, Xia,Grzelak, Michael,Hyde, Lynn A.,Kuvelkar, Reshma,Leach, Prescott T.,Terracina, Giuseppe,Zhang, Lili,Zhang, Qi,Michener, Maria S.,Smith, Brad,Cox, Kathleen,Grotz, Diane,Favreau, Leonard,Mitra, Kaushik,Kazakevich, Irina,McKittrick, Brian A.,Greenlee, William,Kennedy, Matthew E.,Parker, Eric M.,Cumming, Jared N.,Stamford, Andrew W.
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supporting information
p. 3231 - 3248
(2016/05/19)
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- HEXAHYDROPYRROLOTHIAZINE COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R9 are as defined in the specification and which compound has an Αβ production inhibitory effect and may be useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Αβ and typified by Alzheimer-type dementia (AD) or Down's syndrome.
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Page/Page column 43; 44
(2014/02/15)
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- BACE INHIBITORS
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The present invention provides compounds of Formula I useful as BACE inhibitors in the treatment of e.g. Alzheimer's disease : wherein A is selected from the group consisting of; of; R1 is H or F; R2 is H, -OCH3, C1-C3 alkyl,; R3 is H, -CH3, or -OCH3; and R4 is H or F; or a pharmaceutically acceptable salt thereof.
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Page/Page column 16-17
(2014/05/24)
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- PYRROLIDINE-FUSED THIADIAZINE DIOXIDE COMPOUNDS AS BACE 1NHIBITORS, COMPOSITIONS, AND THEIR USE
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In its many embodiments, the present invention provides provides certain iminothiadiazine dioxide compounds, including compounds Formula (I): and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, where in each of W, Z, R1H, R2, R3, R4, ring A, ring B, m, n, p, and- L1 - is as defined herein. The novel compounds of the invention have surprisingly been found to exhibit properties which are expected to render them advantageous as BACE inhibitors and/or for the treatment and prevention of various pathologies related there to. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including Alzheimer?s disease, are also disclosed
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Page/Page column 71-72
(2012/10/18)
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- THIOPHENYL-SUBSTITUTED 2-IMINO-3-METHYL PYRROLO PYRIMIDINONE COMPOUNDS AS BACE-1 INHIBITORS, COMPOSITIONS, AND THEIR USE
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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.
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Page/Page column 88
(2009/12/05)
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