122053-75-2Relevant academic research and scientific papers
4-HYDROXY-PIPERODINE DERIVATIVES
-
, (2008/06/13)
The present invention relates to compounds of the formula STR1 wherein x is--O--,--NH--,--CH 2--,--CH=,--CO 2--,--CONH--,--CON(lower alkyl)--,--S--and--SO 2--; R. sup.1-R. sup.4 are, independently from each other hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, 1-or 2-imidazolyl, 1-(1,2,4-triazolyl) or acetamido;R 5, R 6 are, independently from each other hydrogen, lower-alkyl, hydroxy, lower alkoxy or oxo;R. sup.7-R 10 are, independently from each other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy;n is 0 or 1; and to pharmaceutically acceptable acid addition salts thereof. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers.
Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A
Defauw, Jean M.,Murphy, Marcia M.,Jagdmann Jr., G. Erik,Hu, Hong,Lampe, John W.,Hollinshead, Sean P.,Mitchell, Thomas J.,Crane, Heidi M.,Heerding, Julia M.,Mendoza, José S.,Davis, Jefferson E.,Darges, James W.,Hubbard, Frederick R.,Hall, Steven E.
, p. 5215 - 5227 (2007/10/03)
A series of balanol analogs in which the perhydroazepine ring and the p- hydroxybenzamide moiety were combined into an acyclic linked unit have been prepared and evaluated for their inhibitory properties against the serine/threonine kinase PKC. Several low-micromolar to lownanomolar inhibitors of the α, β'(I), β(II), γ, δ, ε, and η PKC isozymes were prepared. In general, these acyclic balanol analogs were found to be highly selective for PKC over the serine/threonine kinase PKA. The type and number of atoms linking the benzophenone ester to the p-hydroxyphenyl group necessary for optimal PKC inhibition were investigated. The most potent compounds contained a three-carbon linker in which the carboxamide moiety of balanol had been replaced by a methylene group. The effect of placing substituents on the three-carbon chain was also investigated. The preferred compounds contained either a 2-benzene-sulfonamido (6b) or a 1-methyl (21b) substituent. The preferred compounds 6b and 21b were tested against a panel of serine/threonine kinases and found to be highly selective for PKC. The more active enantiomer of 6b, (S)-12b, was 3-10-fold more active than the R- enantiomer against the PKC isozymes. The effect of making the analogs more rigid by making the three-carbon chain part of a five-membered ring, but with retention of the methylene replacement for the carboxamide moiety, led to potent PKC inhibitors including anti-substituted pyrrolidine analog 35b and the most potent PKC inhibitor in the series, anti-substituted cyclopentane analog 29b. The anti cyclopentane analog 29b was a low-micromolar inhibitor of the PMA-induced superoxide burst in neutrophils, and its carboxylic ester was a high-nanomolar inhibitor of neutrophils. Finally esterification of 21b, (S)-12b, and 35b turned these potent PKC inhibitors into low-micromolar inhibitors of neutrophils.
