- 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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Page/Page column 57; 58
(2017/04/11)
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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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Page/Page column 72; 73
(2017/04/11)
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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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Page/Page column 99
(2017/04/11)
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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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Page/Page column 89; 90
(2015/11/17)
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- ORGANIC COMPOUNDS
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The present invention relates to quinazolinone compounds of the formula wherein R2, R3, R5, R6 R7 and R8 are as defined in the specification and in the claims, in free form or in salt form , processes for their preparation and their use as pharmaceuticals, particularly in the treatment of disorders ameliorated by administration of TRPV1 antagonists.
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Page/Page column 46
(2008/06/13)
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- Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
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Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.
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- 3,5-Disubstituted-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof
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Disclosed are 3,5-disubstituted-[1,2,4]-oxadiazoles and analogs thereof, represented by the Formula I: wherein Ar1, R2, A, B and D are defined herein. The present invention relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
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- Analogues of 1-(3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1, 2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase
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The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11 -yl)piperazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.
- Afonso, Adriano,Weinstein, Jay,Kelly, Joseph,Wolin, Ronald,Rosenblum, Stuart B.,Connolly, Michael,Guzi, Timothy,James, Linda,Carr, Donna,Patton, Robert,Bishop, W.Robert,Kirshmeier, Paul,Liu,Heimark,Chen,Nomeir
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p. 1845 - 1855
(2007/10/03)
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