Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists

Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.     

TIE-2/VEGF-R2 SAR and in vitro activity of C3-acyl dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs

Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. Analogs bearing a C3-thiophencarbonyl group were evaluated in enzymatic and cellular biochemical assays; two orally bioavailable analogs were further profiled in functional assays and found to inhibit microvessel growth in rat aortic explant cultures and inhibit Ang-1-stimulated chemotaxis of HUVECs.     

Mixed lineage kinase activity of indolocarbazole analogues.

The MLK1-3 activity for a series of analogues of the indolocarbazole K-252a is reported. Addition of 3,9-bis-alkylthiomethyl groups to K-252a results in potent and selective MLK inhibitors. The in vitro and in vivo survival promoting activity of bis-isopropylthiomethyl-K-252a (16, CEP-11004/KT-8138) is reported.     

Synthesis and structure-activity relationships of novel pyrrolocarbazole lactam analogs as potent and cell-permeable inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

A series of novel pyrrolocarbazole lactams was identified as potent PARP-1 inhibitors in vitro and in a PC12 cellular NAD(+) depletion assay. The SAR trends of substituents at the 3-position, as well as the effect of blocking the indole or lactam NH-groups of the template by methylation or formylation, are discussed in relation to molecular modeling studies.     

Synthesis of constrained benzocinnolinone analogues of CEP-26401 (irdabisant) as potent, selective histamine H3 receptor inverse agonists

A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.     

Synthesis and kinase inhibitory activity of 3'-(S)-epi-K-252a

The 3'-epi diastereomer of K-252a was synthesized with the goal of evaluating the stereochemical requirements of the 3'-sugar alcohol on kinase inhibitory activity. Inverting the 3'-alcohol resulted in a 20 nM inhibitor of VEGFR2 and a 1 nM inhibitor of TrkA tyrosine kinase.     

Candidate MicroRNA Biomarkers in Lupus Nephritis: A Meta-analysis of Profiling Studies in Kidney,Blood and Urine Samples

Molecular Diagnosis & Therapy - Lupus nephritis (LN) is a kidney disease caused by systemic lupus erythematosus in which kidneys are attacked by the immune system. So far, various...     

Sarcocystis hemionilatrantis (Sp. N.) life cycle in mule deer and coyotes.

Fifteen coyotes (Canis latrans) shed sporulated sporocysts in their feces after eating freshly ground skeletal muscles from a mule deer (Odocoileus hemionus hemionus) infected with microscopic-sized cysts of Sarcocystis. Sporocysts were shed intermittently from 12 to 36 days after ingestion of the infected meat. Sporocyst size averaged 14.4 X 9.3 mum. Eleven mule deer fawns orally inoculated with these sporocysts became infected and 9 of 11 died between post-inoculation days (PID) 27 and 63. Clinical signs of anorexia, weight loss, pyrexia and weakness were evident prior to death. A calf (Bos taurus) and two lambs (Ovis aries) orally inoculated with these sporocysts did not become infected and remained healthy throughout the experiments. Similarly, uninoculated control animals consisting of three mule deer fawns, two lambs and one calf remained healthy during the experiment. Preliminary histologic examinations conducted on selected tissues from all animals revealed microscopic-sized schizogonous stages in macrophages, between muscle fibers and near blood vessels in the esophagus, heart, biceps femoris, semi-membranosus, diaphragm and tongue from seven of eight fawns which died between PID 27 and 39. Developing or mature muscle cysts were not found in fawn tissue until PID 60. Sarcocysts were found in the three infected fawns examined after this time. Muscle cysts or earlier schizont stages were not found in tissues from the inoculated or uninoculated calves and lambs. A single muscle cyst was found in one control fawn; the other two control fawns were negative for both muscle cysts and other schizogonous stages. These results established that the life cycle of this species of Sarcocystis can be completed with coyotes as the definitive host and mule deer as the intermediate host. Based on the demonstrated host specificity and earlier findings, the name Sarcocystis hemionilatrantis is proposed for this parasite of mule deer and coyotes.