1319067-40-7Relevant articles and documents
Stepwise Design of γ-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere
Rodríguez Sarmiento, Rosa María,Bissantz, Caterina,Bylund, Johan,Limberg, Anja,Neidhart, Werner,Jakob-Roetne, Roland,Wang, Lisha,Baumann, Karlheinz
, p. 8534 - 8553 (2020/09/21)
Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel CF3-alkoxy groups as bioisosteric replacements of a fluorinated phenyl ring and properties such as lipophilicity, solubility, metabolic stability, and free fraction could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by reducing aromaticity, we prevented phototoxicity. Additional substitution in the triazolopyridine core disturbed the binding to phosphatidylinositol 4-kinase, catalytic β (PIK4CB). We also introduced less lipophilic head heterocycles devoid of covalent binding (CVB) liability. After these changes, further modifications to the trifluoroethoxy bioisosteric replacement allowed rebalancing of properties, such as lipophilicity, and also potency. Our optimization strategy culminated with in vivo active RO7101556 (18B) having excellent properties and being selected as an advanced candidate.
BRIDGED PIPERIDINE DERIVATIVES
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, (2017/07/06)
The present invention relates to a compound of formula (I), wherein Het Ar is a five or six membered hetaryl group, containing one, two or three heteroatoms, selected from N, O or S; R1 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, or lower alkoxy; R2 is lower alkyl substituted by halogen, -CH2-C3-6-cycloalkyl, substituted by one or two substituents, selected from lower alkyl substituted by halogen or halogen, or is lower alkenyl substituted by halogen; R3 is hydrogen, lower alkyl substituted by halogen, lower alkyl, halogen, C3-6-cycloalkyl or lower alkyl substituted by hydroxy; n is 1 or 2; for n = 2, R1 can be independent to each other; Y is CH or N; or to a pharmaceutically active acid addition salt thereof, to a racemic mixture or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. The compounds may be used for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome.
GAMMA SECRETASE MODULATERS
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Page/Page column 37, (2011/08/21)
The invention relates to compounds of formula ( I ) wherein R1/R1' are independently from each other hydrogen, halogen, lower alkoxy or cyano; R2 is lower alkyl, halogen, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by OR, =0, -C(O)O-lower alkyl, -C(O)NH-lower alkyl, cyano, CH2-O-lower alkyl, cycloalkyl, NRR'or is -O-(CH2)o-phenyl optionally substituted by halogen, or is -(CH2)o-phenyl optionally substituted by one, two or three substituents, selected from halogen, -(CH2)o-cyano, lower alkyl, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, C(O)H, -CH2-NH2-, -CH2-NH-C(O)O-lower alkyl, -CH2-NH-C(O)-lower alkyl, -CH2-NH-lower alkyl, -CH2-NH-S(O)2-lower alkyl, lower alkoxy or by lower alkoxy substituted by halogen, or is -(CH2)o-cycloalkyl, or is -(CH2)o-heterocycloalkyl which is optionally substituted by halogen, CF3, lower alkyl, -CH2CN, -C(O)-lower alkyl, -C(O)O-lower alkyl or S(O)2-lower alkyl, or is heteroaryl selected from the group consisting of furanyl, pyrazinyl, pyridinyl, benzooxazolyl or benzoimidazolyl which are optionally substituted by lower alkyl, or is 4-methyl-3,4-dihydro-2H-benzo[l,4]oxazine R and R' are independently from each other hydrogen or lower alkyl, and o is 0 or 1; R3 may occur once or twice and is lower alkyl; A is Formula a), b), c), d), e), f), h), i), j) and Formula k); R2' is hydrogen, lower alkyl, lower alkyl substituted by halogen, C(O)-lower alkyl, S(O)2-lower alkyl or phenyl optionally substituted by halogen; hetaryl is a 5 or 6 membered N, S or O-containing heteroaryl group; n is O, 1, 2 or 3; if n is 2 or 3, R2 may be the same or not; or to pharmaceutically active acid addition salts thereof. The present compounds of formula ( I ) are modulators for amyloid beta and thus, they may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi- infarct dementia, dementia pugilistica and Down syndrome.
