Discovery of Novel 3-Amino-4-alkoxyphenylketones as PDE4 Inhibitors with Improved Oral Bioavailability and Safety against Spatial Memory Impairments

Abstract

To realize PDE4 inhibitors with good developmental potentiality for the treatment of dementia, structure-based optimizations of lead compound FCPR03 resulted in novel aminophenylketones 9c and 9H with low nanomolar potency, which displayed comparable activity to rolipram, satisfactory bioavailability (F% = 36.92 and 42.96% respectively), and good blood–brain barrier (BBB) permeability switching from the cyclopropyl methoxy group to the cyclopropyl methylamine and the amide group to the corresponding ketone. Emetogenicity evaluation on a combined ketamine/xylazine anesthesia mice alternative model demonstrated that 9H displays no emetogenicity even at an oral dose of 5 mg/kg. In contrast, rolipram and roflumilast displayed emetogenicity at an oral dose of 0.5 mg/kg. In acute toxicological evaluation, 9H showed no obvious toxicological effect on mice when administered at oral doses below 625 mg/kg. Further investigations revealed that 9H improves the memory and cognitive impairment of Alzheimer’s disease (AD) model mice induced by Aβ25–35.

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

“…The emetogenic potential of PDE4 inhibitors is assumed to reduce anesthesia duration and the percentage of mice with loss of the righting reflex in the emetogenic mice alternative model. 21,36,37 As shown in Figure 6, the administration of roflumilast, rolipram, and apremilast induced a decrease in the duration of anesthesia. Administering ZL40 2-fold (1 mg/kg) or 10-fold (5 mg/kg) in more significant doses did not induce any effect, which indicated ZL40 had no emetic potential at effective oral dosages.…”

“…The representative compound Z19153 21 (Figure 1), evolution from FCPR03 22 through the replacement of an amide with a ketone and alkoxy with an alkyl amine, exhibited improved oral bioavailability and blood−brain barrier (BBB) permeability. 21 Despite its efficacy, several unfavorable structural features prevent it from being a suitable platform for further lead optimization. A primary concern is related to chemically unstable ethylamine and ketone, which are prone to oxidative metabolism and self-condensation in vivo and pose specific safety considerations.…”

“…The emetogenic potency of PDE4 inhibitors has prevented them from being promoted clinically. Therefore, we further evaluated the emetogenic potential of ZL40 and ZL42 in the combined ketamine/xylazine anesthesia mice alternative model according to the method as previously reported, and using roflumilast (0.5 mg/kg, po), rolipram (0.5 and 1 mg/kg, po), and apremilast (0.5 mg/kg, po) as reference compounds. The emetogenic potential of PDE4 inhibitors is assumed to reduce anesthesia duration and the percentage of mice with loss of the righting reflex in the emetogenic mice alternative model. ,, As shown in Figure , the administration of roflumilast, rolipram, and apremilast induced a decrease in the duration of anesthesia.…”

“…In Vitro Enzymatic Activity Assay. Inhibitory screening assays for PDEs were performed according to our previously reported procedures, 21,22 described in the Supporting Information.…”

“…The following analysis of experimental procedures refers to our previously reported procedures. 21 Effects of ZL40 against Alcohol-Induced Toxicity in SH-SY5Y Cells. The experimental procedures were similar to the reported protocols.…”