Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-O-methyltransferase

Abstract

Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to L-Dopa therapy of Parkinson's disease.

Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders

“…More recently, a number of novel heterocyclic COMT inhibitors were derived from in vitro screening [43]. 1,2,4-oxadiazoles substituted with a pyridine N-oxide motif were found to have reduced toxicity risk and were endowed with longer duration of inhibition.…”

“…1,2,4-oxadiazoles substituted with a pyridine N-oxide motif were found to have reduced toxicity risk and were endowed with longer duration of inhibition. Of note, opicapone [2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, also known as BIA 9-1067] was selected for further pharmacological studies and was found to be a purely peripheral inhibitor of COMT with a unprecedented duration of action [43]. In addition, it presents favourable pharmacodynamics with L-dopa, resulting in stable and sustained plasma L-dopa concentrations over prolonged periods [43].…”

“…Of note, opicapone [2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, also known as BIA 9-1067] was selected for further pharmacological studies and was found to be a purely peripheral inhibitor of COMT with a unprecedented duration of action [43]. In addition, it presents favourable pharmacodynamics with L-dopa, resulting in stable and sustained plasma L-dopa concentrations over prolonged periods [43]. In fact, opicapone is currently under phase III clinical trials for the therapy of Parkinson's disease [44,45].…”

Synthesis of 4-aryl-3-[2-hydroxy-4-(2-cytisin-12-ylethoxy)phenyl]pyrazoles

“…The fact that cytisine derivatives containing a 2-hydroxyethyl substituent in the N(12)-position exhibit analgesic and anti-arrhythmic activity is also interesting [5,6]. Furthermore, 3-(2-hydroxyphenyl)-4-arylpyrazoles are Hsp90 [7,8] and catechol-O-methyltransferase (COMT) inhibitors [9]. Antidepressant activity was also reported for these compounds [10].…”

Diaminoglyoxime as a versatile reagent in the synthesis of bis(1,2,4-oxadiazoles), 1,2,4-oxadiazolyl-quinazolines and 1,2,4-oxadiazolyl-benzothiazinones

“…The derivatives of this oxadiazole have different biological activities such as antiinflammatory, antidiabetic [7], immunosuppressive [8], antimicrobial [9,10], Alzheimer's disease [11], genotoxic activity [12], peptide inhibitory [13], antihyperglycemic [14], anticancer [15][16][17], antitumor [18,19], and antitrypanosomal [20] activity. Furthermore, 1,2,4-oxadiazole derivatives are not only helpful for DNA interaction [21] and inhibiting bacterial infections [22], but also have applications in advanced materials discotic liquid crystals (DLCs) or film forming compounds [23,24].…”