* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download 12.2 Effects of Plasma Stability
Survey
Document related concepts
Pharmacogenomics wikipedia , lookup
Psychopharmacology wikipedia , lookup
Environmental impact of pharmaceuticals and personal care products wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Neuropharmacology wikipedia , lookup
Drug design wikipedia , lookup
Pharmacognosy wikipedia , lookup
Discovery and development of cephalosporins wikipedia , lookup
Discovery and development of proton pump inhibitors wikipedia , lookup
Plateau principle wikipedia , lookup
Drug discovery wikipedia , lookup
Drug interaction wikipedia , lookup
Discovery and development of cyclooxygenase 2 inhibitors wikipedia , lookup
Transcript
Chapter 16 Plasma stability 2014. 1.10. Lee, Sang-Hwi Overview Compound decomposition can be catalyzed in plasma by hydrolytic enzymes. Increased clearance can occur for hydrolyzable substrate compounds. Plasma stability increases with Steric hindrance Electron-withdrawing groups Replacement with a less reactive group. -2- 12.1 Plasma Stability Fundamentals Hydrolytic enzymes in Blood contains ① ② ③ ④ ⑤ Cholinesterase Aldolase Lipase Dehydropeptidase(DPEP) Alkaline and phosphatase The amount of each enzyme is dependent on species, disease state, gender, age, and race. If the compound has affinity for one of these enzymes and it has a hydrolyzable group in the right position, it can be decomposed in the plasma. -3- • Susceptible Functional groups to plasma degradation ① Ester ② Amide ③ Carbamate ④ Lactam ⑤ Lactone ⑥ Sulfonamide • Leads containing these groups, especially peptides and peptide mimetics, should be tested for plasma stability. -4- 12.1 Plasma Stability Fundamentals • • Consequences of Chirality on Plasma Stability Chirality 따라 stability도 차이가 있음. Propranolol : β-blocker(고혈압, 협심증 치료제) 12.1 Plasma Stability Fundamentals -6- 12.1 Plasma Stability Fundamentals -7- 12.2 Effects of Plasma Stability Prodrug enhances permeability or metabolic stability so that high concentrations of the prodrug reach the bloodstream. Antedrugs (soft drug) the opposite of prodrugs. These drugs are active locally but rapidly degrade to an inactive compound once they reach the bloodstream. The purpose of this action is to reduce side effects by minimizing the systemic toxicity of the drug. -8- 12.2 Effects of Plasma Stability • Antedrugs(“soft drug”) - The inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGFl ike growth factor - Target disease : psoriasis (inflammatory skin disease) - Also inhibited matrix metallo proteinases (MMPs). - Introduce the antedrug concept. -9- 12.2 Effects of Plasma Stability (Antedrugs : soft drug) Ciclesonide : lung diseases (asthma and chronic obstructive pulmonary disease) Fluocortin–butyl : Topical anti-inflammatory agent - The gain in therapeutic benefit is limited because of low intrinsic activity - An ester soft drug of the inactive metabolite of fluocortolon. Fluocortolone Loteprednol Etabonate : eye inflammation. An ester soft drug of the inactive metabolite cortienic acid -10- 12.2 Effects of Plasma Stability • • Plasma stability can vary greatly among species rat < dog < human Typically, compounds are less stable in rodents than in humans. The CNS-penetrant Human NK(neurokinin)-1 receptor antagonist. -11- 12.2 Effects of Plasma Stability - Ester prodrug of an aglucosidase 1 inhibitor - Reduces replication of the human immune deficienc virus(HIV). -12- 12.3 Structure modification strategies to improve Plasma stability • Substitute an Amide for an Ester • PKB-α : Protein kinase B • PKA : protein kinase A • PKB is located downstream in the PI-3 kinase • drugs for cancer therapy as effective sensitizers or inducers of apoptosis. -13- 12.3 Structure modification strategies to improve plasma Stability • Increase steric hindrance • • serine protease inhibitors HCMV antiviral activity : human cytomegalovirus -14- 12.3 Structure Modification Strategies to Improve Plasma Stability • Add electron-withdrawing groups to decrease Plasma Stability for Antedrug -15- 12.4 Applications of Plasma Stability Data • Diagnose Poor In Vivo Performance • Alert Teams to a Liability • Prioritize Compounds for In Vivo Animal Studies • Prioritize Synthetic Efforts • Screening of Prodrugs • Guide Structural Modification -16- Plasma stability assay Use our plasma stability assay to measure the degradation of compounds in plasma -17-