Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase.
A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.
Learmonth
David A
DA
Laboratory of Chemistry, Department of Research & Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal.
Palma
P Nuno
PN
Vieira-Coelho
Maria A
MA
Soares-da-Silva
Patrício
P
D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000737:chemistry; D002394:Catechol O-Methyltransferase / Q000737:chemistry; D065098:Catechol O-Methyltransferase Inhibitors; D003205:Computing Methodologies; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
C466310:BIA 3-335; D065098:Catechol O-Methyltransferase Inhibitors; D010879:Piperazines; D002394:Catechol O-Methyltransferase