Oxime carbamate--discovery of a series of novel FAAH inhibitors.

A series of novel oxime carbamates have been identified as potent inhibitors of the key regulatory enzyme of the endocannabinoid signaling system, fatty acid amide hydrolase (FAAH). In this Letter, the rationale behind the discovery and the biological evaluations of this novel class of FAAH inhibitors are presented. Both in vitro and in vivo results of selected targets are discussed, along with inhibition kinetics and molecular modeling studies.(1).

Novel inhibitors of fatty acid amide hydrolase.

A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.

Dihydropyridine neuropeptide Y Y1 receptor antagonists 2. bioisosteric urea replacements.

Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).

Dinapsoline: characterization of a D1 dopamine receptor agonist in a rat model of Parkinson's disease.

Dinapsoline is a new potent, full agonist at D1 dopamine receptors with limited selectivity relative to D2 receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of Parkinson's disease. Dinapsoline produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D1 receptor antagonist SCH-23390, but not by the D2 receptor antagonist raclopride. During a chronic 14-day treatment period in which rats received dinapsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D1:D2 selectivity in vitro than other D1 agonists, the contribution of D2 activity to tolerance was assessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In contrast, when dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D1 and D2 receptors to tolerance, experiments were performed with the selective D1 agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D2 agonist quinpirole plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D1 receptor agonists is influenced by the pattern of drug exposure but not by the D1:D2 selectivity of the agonist.

Dopamine agonists in the treatment of Parkinson s disease past, present and future.

An attempt is made by the author to highlight the important events that laid the foundation of dopamine agonists as a treatment strategy for Parkinson s disease. This debilitating neurodegenerative disorder is long recognized as a result of progressive cell loss in the substantia nigra of the midbrain. The destruction of dopaminergic neurons with projections to the striatum results in the diminishing striatal dopamine levels. Anticholinergic drugs were once widely used to counteract the relative overactivity of cholinergic output from the basal ganglia and the strategy was only met with limited success. The discovery of dopamine depletion and the use of levodopa - a dopamine metabolic precursor, led the way to dopamine replacement therapy . The initial success with levodopa was soon overshadowed by the long-term side effects associated with levodopa. Many new drugs were developed with the hope to replace or strengthen the usefulness of levodopa. Apomorphine and ergot alkaloids have been around for some time; they are recently joined by newer dopamine agonists such as ropinirole and pramipexole. Each of these has its own characteristics and has occupied a place in the pharmacotherapy of Parkinson s disease. In this review older aporphines and ergot alkaloids are discussed first. More emphasis is directed to the side-effect profiles, metabolism and pharmacokinetics in terms of their unique chemical structures. The most recent agonists will be briefly discussed before we move on to the future - the future of emerging novel classes of promising dopaminergic agonists.

Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.

Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors.

Hepatic specificity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may be achieved by efficient first-pass liver extraction resulting in low circulating drug levels, as with lovastatin, or by lower cellular uptake in peripheral tissues, seen with pravastatin. BMY-21950 and its lactone form BMY-22089, new synthetic inhibitors of HMG-CoA reductase, were compared with the major reference agent lovastatin and with the synthetic inhibitor fluindostatin in several in vitro and in vivo models of potency and tissue selectivity. The kinetic mechanism and the potency of BMY-21950 as a competitive inhibitor of isolated HMG-CoA reductase were comparable to the reference agents. The inhibitory potency (cholesterol synthesis assayed by 3H2O or [14C]acetate incorporation) of BMY-21950 in rat hepatocytes (IC50 = 21 nM) and dog liver slices (IC50 = 23 nM) equalled or exceeded the potencies of the reference agents. Hepatic cholesterol synthesis in vivo in rats was effectively inhibited by BMY-21950 and its lactone form BMY-22089 (ED50 = 0.1 mg/kg p.o.), but oral doses (20 mg/kg) that suppressed liver synthesis by 83-95% inhibited sterol synthesis by only 17-24% in the ileum. In contrast, equivalent doses of lovastatin markedly inhibited cholesterol synthesis in both organs. In tissue slices from rat ileum, cell dispersions from testes, adrenal, and spleen, and in bovine ocular lens epithelial cells, BMY-21950 inhibited sterol synthesis weakly in vitro with IC50 values 76- and 188-times higher than in hepatocytes; similar effects were seen for BMY-22089. However, the IC50 ratios (tissue/hepatocyte) for lovastatin and fluindostatin were near unity in these models. Thus, BMY-21950 and BMY-22089 are the first potent synthetic HMG-CoA reductase inhibitors that possess a very high degree of liver selectivity based upon differential inhibition sensitivities in tissues. This cellular uptake-based property of hepatic specificity of BMY-21950 and BMY-22089, also manifest in pravastatin, is biochemically distinct from the pharmacodynamic-based disposition of lovastatin, which along with fluindostatin exhibited potent inhibition in all tissues that were exposed to it.