- Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation
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A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development.
- O'Neill, Brian T.,Beck, Elizabeth M.,Butler, Christopher R.,Nolan, Charles E.,Gonzales, Cathleen,Zhang, Lei,Doran, Shawn D.,Lapham, Kimberly,Buzon, Leanne M.,Dutra, Jason K.,Barreiro, Gabriela,Hou, Xinjun,Martinez-Alsina, Luis A.,Rogers, Bruce N.,Villalobos, Anabella,Murray, John C.,Ogilvie, Kevin,Lachapelle, Erik A.,Chang, Cheng,Lanyon, Lorraine F.,Steppan, Claire M.,Robshaw, Ashley,Hales, Katherine,Boucher, Germaine G.,Pandher, Karamjeet,Houle, Christopher,Ambroise, Claude W.,Karanian, David,Riddell, David,Bales, Kelly R.,Brodney, Michael A.
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p. 4476 - 4504
(2018/05/31)
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- N-[2-(3-AMINO-2,5-DIMETHYL-1,1-DIOXIDO-5,6-DIHYDRO-2H-1,2,4-THIADIAZIN-5-YL)-1,3-THIAZOL-4-YL] AMIDES USEFUL AS BACE INHIBITORS
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The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, wherein the variables R1, R2 and R3/su
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- TETRAHYDROPYRANO[3,4-D][1,3]OXAZIN DERIVATIVES AND THEIR USE AS BACE INHIBITORS
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The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), wherein the variables R1, R2, R3, R4 and X are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
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- N-[2-(2-AMINO-6,6-DISUBSTITUTED-4, 4A, 5, 6-TETRAHYDROPYRANO [3,4-D][1,3] THIAZIN-8A (8H)-YL) -1, 3-THIAZOL-4-YL] AMIDES
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The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variables R1, R2 and R3
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- 2-AMINO-6-METHYL-4,4a,5,6-TETRAHYDROPYRANO[3,4-d][1,3]THIAZIN-8a(8H)-YL-1,3-THIAZOL-4-YL AMIDES
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The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variable R1 is as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
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- Iminothiadiazine Dioxide Compounds as BACE Inhibitors, Compositions and Their Use
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In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula (I): and include stereoisomers thereof, and pharmaceutically acceptable salts of said compounds stereoisomers, wherein each of R1, R2, R3, R4, R5, R9, ring A, ring B, m, n, p, -L1-, -L2-, and -L3- is selected independently and as defined herein. The novel iminothiadiazine dioxide 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 to β-amyloid (“Aβ”) production. 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 in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's disease, are also disclosed.
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Paragraph 0545
(2015/11/16)
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- FUSED MULTI-CYCLIC SULFONE COMPOUNDS AS INHIBITORS OF BETA-SECRETASE AND METHODS OF USE THEREOF
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The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: wherein variables A5, A6, A8, R1, R2, R3, R7, X, Y, n and o of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formula II and sub-formula embodiments thereof, compounds of Formula III, intermediates and processes and methods useful for the preparation of compounds of Formulas I-III, and sub-Formulas thereof.
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- TRICYCLIC COMPOUNDS AS INHIBITORS FOR THE PRODUCTION OF BETA-AMYLOID
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Compounds of formula (I), including pharmaceutically acceptable salts thereof, are set forth herein: formula (I), wherein X is selected from the group of CH2, O, and NR2; m = 0 or 1; R1 at each instance is selected from th
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- FUSED AMINODIHYDROTHIAZINE DERIVATIVES
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A compound represented by the general formula: or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ring A is a C6-14 aryl group or the like, L is —NReCO— or the like (wherein Re is a hydrogen atom or the like), Ring B is a C6-14 aryl group or the like, X is a C1-3 alkylene group or the like, Y is a single bond or the like, Z is a C1-3 alkylene group or the like, R1 and R2 are each independently a hydrogen atom or the like, and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom or the like, has an Aβ production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Aβ and typified by Alzheimer-type dementia.
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Page/Page column 96
(2009/09/05)
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