ABSTRACT
Sickle cell disease (SCD) is a severe, multisystemic hematological disorder that impacts nearly every major organ in adults. The current approved treatments for SCD directly target mutant hemoglobin or address downstream disease pathology. Several compounds targeting reduction of 2,3-DPG by activation of Pyruvate Kinase-R are currently being evaluated in SCD patients. In this study, we genetically engineered a mouse lacking 2,3-DPG on the Townes SCD mouse model background and evaluated the effects of 2,3-DPG loss on disease pathology. Animals lacking 2,3-DPG showed improvements in hematological markers and reductions in RBC sickling relative to native Townes mice, however, minimal difference in organ damage was observed in 2,3-DPG deficient mice compared to native Townes animals. When animals lacking 2,3-DPG were dosed with a compound designed to increase hemoglobin oxygen affinity, oxygen delivery related toxicity was observed.
Subject(s)
Anemia, Sickle Cell , Adult , Humans , Mice , Animals , 2,3-Diphosphoglycerate , Anemia, Sickle Cell/genetics , Hemoglobins/analysis , Phenotype , OxygenSubject(s)
Anemia, Sickle Cell/blood , Hemoglobins/metabolism , Animals , Disease Models, Animal , MiceABSTRACT
Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered.
Subject(s)
Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Obesity/drug therapy , Proline/pharmacokinetics , Proline/therapeutic use , Serotonin 5-HT2 Receptor Agonists , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Amides/therapeutic use , Animals , Anti-Obesity Agents/pharmacology , Brain/metabolism , Dogs , Eating/drug effects , Humans , Proline/analogs & derivatives , Proline/pharmacology , Rats , Receptor, Serotonin, 5-HT2C/metabolism , Structure-Activity RelationshipABSTRACT
Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose-responsive in vivo efficacy in our pre-clinical food intake model.
