Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles.

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.

Novel thiazole-based heterocycles as selective inhibitors of fibrinogen-mediated platelet aggregation.

The synthesis and biological activity of novel thiazole-based heterocycles as inhibitors of thrombin-induced human platelet aggregation are described. Further evaluation of selected compounds show they inhibit platelet aggregation as stimulated by a variety of agonists. The more active compounds also were found to inhibit fibrinogen binding to platelets. To further delineate the mechanism of action of these compounds, direct binding studies with the purified glycoprotein (GP) IIb/IIIa receptor were performed. Flow cytometry analyses of 24 and 32 indicate that these compounds block the activation process of the GPIIb/IIIa receptor without denaturing the integrin receptor. On the basis of these studies, 32 exhibited the best profile as a novel nonpeptide inhibitor of fibrinogen-mediated platelet aggregation.

Novel thieno[2,3-b]- and [3,4-b]pyrans as potassium channel openers. Thiophene systems--XVII.

The syntheses and antihypertensive activity of the thieno[3,4-b]pyran and thieno[2,3-b]pyran isosteres of the potassium channel opener (PCO) RWJ 26629 (+/- 2a) are reported. While the unsubstituted thiophene derivatives were active at 20 mg/kg, introduction of a strong electron withdrawing group in the 2-position of the thieno[3,2-b] series increased potency. Similar substitution on the thieno[3,4-b] series significantly lowered potency. Compounds 26 and 30 are approximately 5-fold more potent than the prototypic PCO cromakalim (+/- 1).

Thiophene systems. 14. Synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxythieno[3,2-b]pyrans and related compounds as new potassium channel activators.

The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.

Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused heterocycles with calcium channel blocking and local anesthetic activity.

A series of imidazo-fused heterocycles substituted with an aryloxy)alkylamine side chain were prepared as modifications to butoprozine (I) and found to possess calcium channel blocking activity similar in potency to that of bepridil in trachea smooth muscle and similar to that of verapamil in nitrendipine binding affinity in rabbit cardiac muscle. Of the various imidazo-fused heterocycles prepared, the imidazo[1,2-a]pyridines were also found to be potent local anesthetic agents. While most compounds in this series were equipotent to lidocaine in our initial screen, compounds 2 and 35 showed local anesthetic activity approximately 100 times more potent than lidocaine in our preliminary assays. These compounds represent a novel structural class of local anesthetic agents, and compound 2 is under further investigation.

Synthesis of (aryloxy)alkylamines. 1. Novel antisecretory agents with H+K+-ATPase inhibitory activity.

A series of heterocyclic (aryloxy)alkylamines of structures II and III were prepared and found to possess gastric antisecretory activity. Of the variety of substituted thiazoles, benzoxazoles, and benzothiazoles prepared, thiazole 18, benzoxazole 32, and benzothiazole 47 exhibited gastric antisecretory potency comparable to that of ranitidine in vivo in the pylorous ligated rat model. In an isolated rabbit parietal system, the series of thiazoles, benzoxazoles, and benzothiazoles also demonstrated similar potency to that of ranitidine toward the inhibition of both histamine-stimulated and dcAMP-stimulated uptake of amino[14C]pyrine. These compounds inhibited the H+K+-sensitive ATPase enzyme in isolated gastric microsomes. A direct correlation existed between inhibition of 14C uptake, in vivo antisecretory activity, and inhibition of the H+K+-ATPase enzyme. The more potent antisecretory compounds 18, 32, and 47 were also the more potent enzyme inhibitors. These data suggest that the mechanism responsible for the observed in vitro and in vivo gastric antisecretory activity, in these series of compounds, is a consequence of the inhibition of the H+K+-sensitive ATPase enzyme.

4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity.

alpha-Melanocyte-stimulating hormone (alpha-MSH) reversibly darkens frog skins by stimulating melanosome movement (dispersion) within melanophores. Heat-alkali treatment of alpha-MSH results in prolonged biological activity of the hormone. Quantitative gas chromatographic analysis of the hydrolyzed heat-alkali-treated peptide revealed partial racemization particularly at the 4(methionine) and 7(phenylalanine) positions. [Nle4]-alpha-MSH, a synthetic analogue of alpha-MSH, reversibly darkens frog skins and also exhibits prolonged activity after heat-alkali treatment. Synthesis of [Nle4, D-Phe7]-alpha-MSH provided an analogue with prolonged biological activity identical to that observed with heat-alkali-treated alpha-MSH or [Nle4]-alpha-MSH. [Nle4, D-Phe7]-alpha-MSH was resistant to enzymatic degradation by serum enzymes. In addition, this peptide exhibited dramatically increased biological activity as determined by frog skin bioassay, activation of mouse melanoma adenylate cyclase, and stimulation of mouse melanoma cell tyrosinase activity. This Nle4, D-Phe7 synthetic analogue of alpha-MSH is a very porent melanotropin, 26 times as potent as alpha-MSH in the adenylate cyclase assay. The resistance of the peptide to enzymatic degradation and its extraordinarily potent and prolonged biological activity should make this analogue of alpha-MSH an important molecular probe for studying the melanotropin receptors of both normal and abnormal (melanoma) melanocytes.