- Aminoguanidine hydrazone derivatives as non-peptide NPFF1 receptor antagonists reverse opioid induced hyperalgesia
-
Neuropeptide FF receptors (NPFF1R and NPFF2R) and their endogenous ligand Neuropeptide FF have been shown previously to display anti-opioid properties and to play a critical role in the adverse effects associated with chronic administrations of opiates including the development of opioid-induced hyperalgesia and analgesic tolerance. In this work, we sought to identify novel NPFF receptors ligands by focusing our interest on a series of heterocycles as rigidified non-peptide NPFF receptor ligands, starting from already described aminoguanidine hydrazones (AGH's). Binding experiments and functional assays highlighted AGH 1n and its rigidified analog 2-amino-dihydropyrimidine 22e for in vivo experiments. As earlier shown with the prototypical dipeptide antagonist RF9, both 1n and 22e reduced significantly the long lasting fentanyl-induced hyperalgesia in rodents. Altogether these data indicate that AGH rigidification maintains nanomolar affinities for both NPFF receptors, while improving antagonist character towards NPFF1R.
- Hammoud, Hassan,Elhabazi, Khadija,Quillet, Rapha?lle,Bertin, Isabelle,Utard, Valérie,Laboureyras, Emilie,Bourguignon, Jean-Jacques,Bihel, Frederic,Simonnet, Guy,Simonin, Frederic,Schmitt, Martine
-
-
- 2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical application
-
The invention provides a 2-polysubstituted aromatic ring-pyrimidine derivative, an optical isomer of the derivative or a medically acceptable salt or solvate of the derivative, and application of the compound, the optical isomer of the derivative or the medically acceptable salt or solvate of the derivative in preparing antineoplastic medicine. According to the 2-polysubstituted aromatic ring-pyrimidine derivative, by adopting N-substituted pyridine-2-minopyrimidine as a lead compound obtained based on virtual screening of a structure, a series of brand new small molecule Chk1 inhibitors are designed and synthesized, and a Chk1 kinase inhibitory activity test of a molecular level is conducted on the compound. Experiments prove that the compound is a Chk1 inhibitor with a strong antitumous effect, Chk1 kinase inhibitory activity and a prospect, and new cancer treating medicine, and can be used for treating solid tumor or leukemia related with human or animal cell proliferation. The 2-polysubstituted aromatic ring-pyrimidine derivative has a structure shown in the general formula I.
- -
-
Paragraph 0165; 0248; 0249; 0250; 0251
(2017/05/20)
-
- Reduction of CYP450 inhibition in the 4-[(1H-imidazol-4-yl)methyl] piperidine series of histamine H3 receptor antagonists
-
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
- Berlin, Michael,Ting, Pauline C.,Vaccaro, Wayne D.,Aslanian, Robert,McCormick, Kevin D.,Lee, Joe F.,Albanese, Margaret M.,Mutahi, Mwangi W.,Piwinski, John J.,Shih, Neng-Yang,Duguma, Luli,Solomon, Daniel M.,Zhou, Wei,Sher, Rosy,Favreau, Leonard,Bryant, Matthew,Korfmacher, Walter A.,Nardo, Cymbelene,West Jr., Robert E.,Anthes, John C.,Williams, Shirley M.,Wu, Ren-Long,Susan She,Rivelli, Maria A.,Corboz, Michel R.,Hey, John A.
-
p. 989 - 994
(2007/10/03)
-