175965-65-8Relevant 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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Page/Page column 40, (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.
Synthetic access to 2-amido-5-aryl-8-methoxy-triazolopyridine and 2-amido-5-morpholino-8-methoxy-triazolopyridine derivatives as potential inhibitors of the adenosine receptor subtypes
Nettekoven, Matthias,Puellmann, Bernd,Schmitt, Sebastien
, p. 1649 - 1652 (2007/10/03)
Two versatile and complementary synthetic strategies towards 2-amido-5-aryl-8-methoxy-triazolopyridine derivatives and 2-amido-5-morpholino-8-methoxy-triazolopyridine derivatives in five steps are presented. The key step in each synthetic route can be constituted as the formation of the respective triazolopyridine derivative precursors in 78% and 57% yield, respectively, through an intermediately formed 4H-[1,2,4]oxadiazol-5-one. The final Suzuki coupling/amidation allowed the straightforward access to the desired triazolopyridine derivatives which have not been described previously. Notably, these triazolopyridine-scaffold bears three vectors of diversity which offer maximum flexibility in design and combinatorial synthesis of molecules with a potentially useful inhibitory activity towards adenosine receptor subtypes.