Laszlo Erno Kiss

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

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 Parkinsons disease.

Atrial Antifibrillatory Effects of Structurally Distinct IKur Blockers 3-[(Dimethylamino)methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one and 2-Phenyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-yl-ethanol in Dogs with Underlying Heart Failure

Drug discovery efforts have focused recently on atrial-selective targets, including the Kv1.5 channel, which underlies the ultrarapid delayed rectifier current, IKur, to develop novel treatments for atrial fibrillation (AF). Two structurally distinct compounds, a triarylethanolamine TAEA and an isoquinolinone 3-[(dimethylamino)-methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (ISQ-1), blocked IKur in Chinese hamster ovary cells expressing human Kv1.5 with IC50 values of 238 and 324 nM, respectively. In anesthetized dogs, i.v. infusions of TAEA and ISQ-1 elicited comparable 16% increases in atrial refractory period, with no effect on ventricular refractory period or QTc interval. Plasma concentrations at end infusion for TAEA and ISQ-1 were 58.5 ± 23.6 and 330.3 ± 43.5 nM, respectively. The abilities of TAEA and ISQ-1 to terminate AF, with comparison to the rapidly activating component of delayed rectifier potassium current blocker (+)-N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4′-piperidin)-6-yl]methanesulfonamide] monohydrochloride (MK-499) and the class IC 1-[2-[2-hydroxy-3-(propylamino)-propoxy]phenyl]-3-phenyl-1-propanone (propafenone), were assessed in conscious dogs with heart failure and inducible AF (entry criterion). All test agents administered in i.v. bolus regimens terminated AF in at least half of animals tested; conversely no agent was universally effective. MK-499, ISQ-1, TAEA, and propafenone terminated AF in five of six, four of seven, four of six, and five of six animals at plasma concentrations of 32.6 ± 18.7, 817 ± 274, 714 ± 622, and 816 ± 240 nM, respectively. Directed cardiac electrophysiologic studies in anesthetized dogs using i.v. bolus (consistent with AF studies) plus infusion regimens with TAEA and ISQ-1 demonstrated significant increases in atrial refractory period (12–15%), A-H and P-A intervals, but no effects on ventricular refractory period, H-V, and HEG intervals. The demonstration of AF termination with TAEA and ISQ-1 in the dog heart failure model extends the profile of antiarrhythmic efficacy of Kv1.5 blockade.

Medicinal chemistry of catechol O-methyltransferase (COMT) inhibitors and their therapeutic utility.

Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinsons disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors.

Efficient Synthesis of 2-(Trifluoromethyl)nicotinic Acid Derivatives from Simple Fluorinated Precursors

Novel routes to 2-trifluoromethyl-nicotinic acid derivatives have been developed involving synthesis of the pyridine ring. These pyridyl compounds serve as key intermediates in the manufacture of the recently discovered COMT inhibitor, 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)pyridine 1-oxide.

CHAPTER 4:Catechol‐O‐Methyl‐Transferase Inhibitors: Present Problems and Relevance of the New Ones

Levodopa, in association with a DOPA decarboxylase inhibitor (e.g., carbidopa or benserazide) has for many years been the undisputed gold standard drug for the symptomatic treatment of Parkinson’s disease (PD). However, given its rapid disposition and elimination in the periphery, it was hypothesized that significant enhancements in levodopa bioavailability and clinical efficacy could be achieved through co‐adjuvant therapy with a catechol‐O‐methyl‐transferase (COMT) inhibitor. Early attempts, dating back to the late 1950s, to discover COMT inhibitors were generally hampered by their lack of in vivo efficacy, target selectivity or by considerable toxicity. It was not until the late 1990s that entacapone and tolcapone, representatives of a new class of potent COMT inhibitors (nitrocatechol derivatives), made their way to clinical practice for the treatment of PD. Even though these drugs have since contributed to an increase in the usefulness of levodopa therapy, each of them presents known limitations, namely concerning their clinical efficacy and safety. The unmet medical need for more efficacious and safer COMT inhibitors has motivated intense research in this field over the last decade. Opicapone is the first, third‐generation COMT inhibitor among the nitrocatechol derivatives under clinical development, and demonstrates superior pharmacodynamic and safety profiles in humans, over previous drugs. In this chapter, we review the major advances in this field, summarize the relevant non‐clinical and clinical human pharmacology and discuss new insights into the mechanism of action of opicapone.

Design, synthesis, and structure–activity relationships of 1,3,4-oxadiazol-2(3H)-ones as novel FAAH inhibitors

Novel 5-aryloxy substituted 3-phenyl-1,3,4-oxadiazol-2(3H)-ones were prepared and identified as potent inhibitors of FAAH. In vitro SAR are discussed. Structural variations of the selected lead compound were explored in order to optimise in vivo efficacy and selectivity.

The chemistry of catechol-O-methyltransferase inhibitors.

Despite several drawbacks, levodopa (L-dopa) remains the gold standard drug for treatment of the symptoms of Parkinsons disease (PD). L-dopa is a pro-drug of dopamine and is used to elevate striatal levels of the neurotransmitter. One approach to provide a more continuous and sustained delivery of dopamine has targeted one of the principal enzymes responsible for metabolic deactivation of L-dopa, namely catechol-O-methyltransferase (COMT). The chapter will provide a perspective of the medicinal chemistry behind the discovery of several COMT inhibitors and discuss how certain physicochemical parameters, including aqueous solubility and lipophilicity, are thought to influence pharmacokinetic properties such as absorption, distribution, and bioavailability.

Synthesis and structure–activity relationships of ionizable 1,3,4-oxadiazol-2(3H)-ones as peripherally selective FAAH inhibitors with improved aqueous solubility

Abstract Novel 5-(2,4-difluorophenoxy)-3-aryl-1,3,4-oxadiazol-2(3H)-ones were prepared and in vivo SAR are discussed. Ionisable substituents on the N-phenyl ring provided compounds with significantly improved aqueous solubility. In addition, these analogues retained equivalent or improved potency against FAAH enzyme compared to the parent phenols 2–3. FAAH inhibition by the 2-(piperazin-1-yl)ethyl and 3-(piperazin-1-yl)propyl derivatives 24 and 30 was confined to the periphery in mice (30 mg/kg), whereas hepatic FAAH activity was inhibited by over 90%.

Discovery of a Potent, Long‐Acting, and CNS‐Active Inhibitor (BIA 10‐2474) of Fatty Acid Amide Hydrolase

Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of heterocyclic‐N‐carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs). Lead optimization efforts carried out with benzotriazolyl‐ and imidazolyl‐N‐carboxamide series led to the discovery of clinical candidate 8 l (3‐(1‐(cyclohexyl(methyl)carbamoyl)‐1H‐imidazol‐4‐yl)pyridine 1‐oxide; BIA 10‐2474) as a potent and long‐acting inhibitor of FAAH. However, during a Phase I clinical trial with compound 8 l, unexpected and unpredictable serious neurological adverse events occurred, affecting five healthy volunteers, including the death of one subject.