Stepwise Design of gamma-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere
Sarmiento, RMR; Bissantz, C; Bylund, J; Limberg, A; Neidhart, W; Jakob-Roetne, R; Wang, L; Baumann, K; ,
| HERO ID | 7073878 |
|---|---|
| In Press | No |
| Year | 2020 |
| Title | Stepwise Design of gamma-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere |
| Authors | Sarmiento, RMR; Bissantz, C; Bylund, J; Limberg, A; Neidhart, W; Jakob-Roetne, R; Wang, L; Baumann, K; , |
| Journal | Journal of Medicinal Chemistry |
| Volume | 63 |
| Issue | 15 |
| Page Numbers | 8534-8553 |
| Abstract | Starting from RO6800020 (1), our former gamma-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 beta (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. |
| Doi | 10.1021/acs.jmedchem.0c00909 |
| Pmid | 32706964 |
| Wosid | WOS:000562941200042 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Scopus URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089607772&doi=10.1021%2facs.jmedchem.0c00909&partnerID=40&md5=f350ce7f85fd5275bcb730e65ddd15ab |
| Is Public | Yes |
| Language Text | English |
| Keyword | 2 bromo 8 (1,1,1 trifluoropropan 2 yloxy) [1,2,4]triazolo[1,5 a]pyridine; 2 bromo 8 (2,2,2 trifluoroethoxy) [1,2,4]triazolo[1,5 a]pyridine; 2 bromo 8 (2,2,3,3,3 pentafluoropropoxy) [1,2,4]triazolo[1,5 a]pyridine; 2 bromo 8 (3,3,3 trifluoropropoxy) [1,2,4]triazolo[1,5 a]pyridine; 2 bromo 8 (4,4,4 trifluorobutoxy) [1,2,4]triazolo[1,5 a]pyridine; 2 bromo 8 (oxetan 3 ylmethoxy) [1,2,4]triazolo[1,5 a]pyridine; 2 bromo 8 (trifluoromethoxy) [1,2,4]triazolo[1,5 a]pyridine; 2 bromo 8 methoxy [1,2,4]triazolo[1,5 a]pyridine; 3 (3 methyl 1,2,4 oxadiazol 5 yl) 3 azabicyclo[3.2.1]octan 8 amine; 3 (3 methyl 1,2,4 thiadiazol 5 yl) 3 azabicyclo[3.2.1]octan 8 amine; 3 (3 methylisothiazol 5 yl) 3 azabicyclo[3.2.1]octan 8 amine; 3 (3 methylisoxazol 5 yl) 3 azabicyclo[3.2.1]octan 8 amine; 3 (5 methyl 1,3,4 oxadiazol 2 yl) 3 azabicyclo[3.2.1]octan 8 amine; 3 (6 methylpyrimidin 4 yl) 3 azabicyclo[3.2.1]octan 8 amine; 3 [2 (trifluoromethyl)pyridin 4 yl] 3 azabicyclo[3.2.1]octan 8 amine; 8 (trifluoromethoxy) [1,2,4]triazolo[1,5 a]pyridin 2 amine; 8 methoxy n [3 (3 methyl 1,2,4 thiadiazol 5 yl) 3 azabicyclo[3.2.1]octan 8 yl] [1,2,4]triazolo[1,5 a]pyridin 2 amine; 8 methoxy [1,2,4]triazolo[1,5 a]pyridin 2 amine; gamma secretase inhibitor; n[3 (3 methyl 1,2 thiazol 5 yl) 3 azabicyclo[3.2.1]octan 8 yl] 8 [1,1,1 trifluoropropan 2 yl]oxy [1,2,4]triazolo[1,5 a]pyridin 2 amine; n[3 (3 methyl 1,2,4 thiadiazol 5 yl) 3 azabicyclon[3.2.1]octan 8 yl] 8 (3,3,3 trifluoropropoxy) [1,2,4]triazolo[1,5 a]pyridin 2 amine; n[3 (3 methyl 1,2,4 thiadiazol 5 yl) 3 azabicyclon[3.2.1]octan 8 yl] 8 (4,4,4 trifluorobutoxy) [1,2,4]triazolo[1,5 a]pyridin 2 amine; n[3 (3 methyl 1,2,4 thiadiazol 5 yl) 3 azabicyclon[3.2.1]octan 8 yl] 8 (oxetan 3 ylmethoxy) [1,2,4]triazolo[1,5 a]pyridin 2 amine; n[3 (3 methyl 1,2,4 thiadiazol 5 yl) 3 azabicyclon[3.2.1]octan 8 yl] 8 [1,1,1 trifluoropropan 2 yl]oxy [1,2,4]triazolo[1,5 a]pyridin 2 amine; n[3 (3 methyl 1,2,4 thiadiazol 5 yl) 3 azabicyclo[3.2.1]octan 8 yl] 8 (trifluoromethoxy) [1,2,4]triazolo[1,5 a]pyridin 2 amine; pyridine derivative; ro 6800020; tert butyl n[3 (5 methyl 1,3,4 oxadiazol 2 yl) 3 azabicyclo[3.2.1]octan 8 yl]carbamate; tert butyl(3 cyano 3 azabicyclo[3.2.1]octan 8 yl)carbamate; tert butyl[3 (3 methylisoxazol 5 yl) 3 azabicyclo[3.2.1]octan 8 yl]carbamate; tert butyl[3 [2 (trifluoromethyl)pyridin 4 yl] 3 azabicyclo[3.2.1]octan 8 yl]carbamate; unclassified drug; amyloid beta protein; enzyme inhibitor; secretase; animal experiment; animal tissue; area under the curve; Article; central nervous system; controlled study; covalent bond; drug clearance; drug efficacy; drug half life; drug penetration; drug potency; drug protein binding; drug solubility; drug stability; enzyme inhibition; human; human cell; in vivo study; lipophilicity; metabolic stability; mouse; nonhuman; phototoxicity; animal; cell line; chemistry; drug design; drug effect; metabolism; molecular model; nerve cell; transgenic mouse; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Cell Line; Drug Design; Enzyme Inhibitors; Humans; Mice, Transgenic; Models, Molecular; Neurons |