Design, Synthesis, ADME Properties, and Pharmacological Activities of β‐Alanyl‐D‐histidine (D‐Carnosine) Prodrugs with Improved Bioavailability

摘要: β-Alanyl-D-histidine (D-CAR, the enantiomer of natural dipeptide carnosine) is a selective and potent sequestering agent reactive carbonyl species (RCS) that stable against carnosinase, but poorly absorbed in gastrointestinal tract. Herein we report drug discovery approach aimed at increasing oral bioavailability D-CAR. In our study designed, synthesized, evaluated series novel lipophilic D-CAR prodrugs. The considered prodrugs can be divided into two categories: 1) derivatives with both terminal groups modified, which carboxyl terminus always esterified while amino protected by an amidic (N-acetyl derivatives) or carbamate (ethyloxy benzyloxy function; 2) only one alkyl esters as well derivatives. were designed considering their expected lipophilicity hydrolysis predicted docking simulations on most important human carboxylesterase (hCES1). stability metabolic profile studied incubating them rat serum liver fractions. octyl ester (compound 13) was chosen candidate for further pharmacological studies due to its rapid bioactive metabolite vitro. Pharmacokinetic rats confirmed vitro data demonstrated increased 2.6-fold if given relative Compound 13 then found dose-dependently (at daily doses 3 30 mg kg(-1) equivalent D-CAR) decrease development hypertension dyslipidemia, restore renal functions Zucker fa/fa obese rats, inhibit carbonylation process (AGEs pentosidine) oxidative stress (urinary 8-epi-prostaglandin F2α nitrotyrosine). A plausible mechanism underlying protective effects RCS sequestration, evidenced significant increase level adduct between CAR 4-hydroxy-trans-2-nonenal (HNE, main generated lipid oxidation) urine treated animals.