1,3-Disubstituted benzazepines as neuropeptide Y Y1 receptor antagonists.

A novel class of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Through a blind screening we found the compound 1-N-(3-(N'-(tert-butoxycarbonyl)amino)benzyl)-7-methoxy-(3-(3)-methyl ureido)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (9: IC50 = 1.6 microM). Chemical modifications of 9 gave a potent NPY Y1 antagonist 3-(N-(4-hydroxyphenyl)-N'-methylguanidino)-1-N-(3-(N'-(tert-butoxy carbonyl)amino)benzyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (14c: IC5(0=43 nM), which had no affinity for NPY Y2 and Y5 receptors.

1,3-Disubstituted benzazepines as novel, potent, selective neuropeptide Y Y1 receptor antagonists.

A novel series of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Chemical modification of the R(1) and R(3) substituents in structure 1 (Chart 1) yields several compounds that show high affinity for the Y1 receptor (K(i) values of less than 10 nM). SAR studies revealed that introduction of an isopropylurea group at R(1) and a 3-(benzo-condensed-urea) group, 3-(fluorophenylurea) group, or a 3-(N-(4-hydroxyphenyl)guanidine) group at R(3) in structure 1 afforded potent and subtype-selective NPY Y1 receptor antagonists. 3-(3-(Benzothiazol-6-yl)ureido)-1-N-(3-(N'-(3-isopropylureido++ +))benzyl )-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (21), which was one of the most potent derivatives, competitively inhibited specific [(125)I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC cells (K(i) = 5.1 nM). 21 not only inhibited the Y1 receptor-mediated increase in cytosolic free Ca(2+) concentration in SK-N-MC cells but also antagonized the Y1 receptor-mediated inhibitory effect of peptide YY on gastrin-induced histamine release in rat enterochromaffin-like cells. 21 showed no significant affinity in 17 receptor binding assays including Y2, Y4, and Y5 receptors.

Crystal structure of human secretory phospholipase A2-IIA complex with the potent indolizine inhibitor 120-1032.

Phospholipase A2 is a key enzyme in a number of physiologically important cellular processes including inflammation and transmembrane signaling. Human secretory phospholipase A2-IIA is present at high concentrations in synovial fluid of patients with rheumatoid arthritis and in the plasma of patients with septic shock. Inhibitors of this enzyme have been suggested to be therapeutically useful non-steroidal anti-inflammatory drugs. The crystal structure of human secretory phospholipase A2-IIA bound to a novel potent indolizine inhibitor (120-1032) has been determined. The complex crystallizes in the space group P3121, with cell dimensions of a = b = 75.8 A and c = 51.3 A. The model was refined to an R-factor of 0. 183 for the intensity data collected to a resolution of 2.2 A. It was revealed that the inhibitor is located near the active site and bound to the calcium ion. Although the binding mode of the 120-1032 inhibitor to human secretory phospholipase A2-IIA is similar to that previously determined for an indole inhibitor LY311299, the specific interactions between the enzyme and the inhibitor in the present complex include the oxycarboxylate group which was introduced in this inhibitor. The oxycarboxylate group in 120-1032 is coordinated to the calcium ion and included in the water-mediated hydrogen bonding to the catalytic Asp49. In addition, the ethyl group in 120-1032 gains hydrophobic contacts with the cavity wall of the hydrophobic channel of the enzyme.

Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509.

A novel series of CCK-B/gastrin receptor antagonists-ureidomethylcarbamoylphenylketone derivatives-were designed, synthesized, and evaluated for activity. Structure-activity relationship studies revealed the importance of a carboxylic acid at substituent R2 and tert-butoxycarbonyl group at R1 in structure A. Compound 7a (S-0509) showed remarkable affinity for the CCK-B/gastrin receptor and a subtype selectivity profile in vitro. Administration (id) of 7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats with an ED50 value of 0.014 mg/kg. Furthermore, 7a proved to have poor blood-brain permeability by its small effect on enhancement of morphine analgesia. Thus, S-0509 has an increase in selectivity for the peripheral effects of gastrin antagonism from the central effects of CCK-B antagonism.

Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with decreased hydrophobicity.

In order to study structure-activity relationships of the previously reported dual histamine H2 and gastrin receptor antagonists and also to improve their low oral absorbability, we tried two chemical modifications. One tried to decrease the high hydrophobicity of the parent hybrid compounds to an appropriate level by incorporating a hydrophilic group into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) involved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H2A, or a phenyl ring at the C5 of the benzodiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H2A. The latter (type II) involved hybrid compounds with the C5-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, ([2-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl] ethylcarbamoyl]methyl)carbamic acid 3-[3-[5-(3-hydroxyphenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiaz epin-3-yl]ureido]benzyl ester (18), showed potent dual histamine H2 and gastrin receptor antagonistic activity, whereas others resulted in a significant decrease of histamine H2 receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild's rat method, however, did not suggest any notable improvement in oral absorbability.

Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with modified benzodiazepine skeletons.

Three different types of dual histamine H2 and gastrin receptor antagonists, e.g. those bearing a benzazepine, benzoxazepine, or benzothiazepine skeleton instead of the benzodiazepine one as a gastrin receptor antagonistic moiety were synthesized to reduce high hydrophobicity of parent compounds and evaluated for the dual activities. These skeletal modifications significantly potentiated the binding affinity of dual antagonists with histamine H2 receptor but markedly diminished their binding affinity with the gastrin receptor and the gastrin versus CCK-A receptor selectivity. We evaluated in vivo gastric acid antisecretory activities for some representative compounds by the rat pylorus ligation method for 10 mg kg(-1) dose by oral route. However, they exerted only low inhibitory activities for oral dose with % inhibition values ranging between 32 and 53%.

Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with noncyclic gastrin receptor antagonistic moieties.

In order to study structure-activity relationships of dual histamine H2 and gastrin receptor antagonists as well as to improve their low oral absorbability, their prototype benzodiazepine gastrin receptor antagonistic moieties were altered to a conformationally flexible noncyclic dipeptide equivalent. This skeletal modification significantly potentiated the binding affinity of hybrid compounds for the histamine H2 receptor, whereas their affinity for the gastrin receptor and receptor selectivity over the CCK-A receptor varied widely with the substituents on the gastrin moiety. Among them, [3-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl]p ropyl carbamic acid 3-[3-([(3-methoxyphenyl)[(methylphenylcarbamyl)methyl]carbamoyl]me thyl)ureido]benzyl ester (7a) showed the highest dual histamine H2 and gastrin receptor antagonistic activities. It also displayed distinct gastric acid antisecretory activity in vivo for two assays, namely, Schild's rat method by i.d. administration and the rat pylorus ligation method by oral administration. With the latter case, dose-response relationships were observed for the first time, suggesting its substantially improved oral absorbability. However, 7a did not display distinct in vivo gastric acid antisecretory activity for the assay with Heidenhain pouch dogs.

Potent and subtype-selective CCK-B/gastrin receptor antagonists: 2,4-dioxo-1,5-benzodiazepines with a plane of symmetry.

A series of CCK-B/gastrin receptor antagonists, 2,4-dioxo-1,5-benzodiazepine derivatives with a plane of symmetry, were designed, synthesized, and evaluated for antagonistic activity. Structure-activity relationship studies revealed that carbonylmethyl groups at both N-1 and N-5 positions and hydrophilic groups, such as the carboxyl group on the benzene ring attached to the ureido group at the C-3 position, brought about potent affinity and subtype selectivity for CCK-B/gastrin receptors. Several compounds showed excellent in vivo inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats.

Synthesis and biological evaluation of a new reversely linked type of dual histamine H2 and gastrin receptor antagonist.

In an attempt to improve the low oral absorbability of previously reported dual histamine H2 and gastrin receptor antagonists, compounds of a different type were synthesized and evaluated for biological activity. These new compounds bear a histamine H2 receptor antagonist (H2A) pharmacophore moiety attached to a gastrin receptor antagonist (GA) pharmacophore moiety in a reversed manner, namely the head-to-head manner, different from the previously reported head-to-tail manner. These new hybrid compounds were classified into three types: type I, the regular amide type bearing a roxatidine moiety; type II, the reversed amide type bearing a roxatidine moiety; and type III, hybrid compounds bearing a famotidine moiety directly connected to a GA moiety without a spacer. Among them, only (R)-1-[3-(N'-(4-[2-(N-aminosulfonylamidino)ethylthiomethyl] thiazol-2-yl) guanidinomethyl)phenyl]-3- (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl) ure a (42), belonging to type III, showed a weak but distinct histamine H2 receptor-antagonistic activity as well as a modest gastrin receptor-antagonistic activity. Of most importance was the finding that this compound showed a weak but clearly improved in vivo oral antigastric acid secretory activity as a result of the structural changes, including the decreased molecular weight.

Potent inhibitors of secretory phospholipase A2: synthesis and inhibitory activities of indolizine and indene derivatives.

Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.

A novel class of platelet activating factor (PAF) antagonists. II. Modification of the 2-position of the glycerol backbone of PAF-sulfonamide isosteres.

In a continuing effort to obtain more potent platelet activating factor (PAF) antagonists, we tried to synthesize a series of PAF-sulfonamide isosteres in which the substituent at the 2-position was modified to an acetoxy equivalent other than the methoxy group. These modifications produced highly active PAF antagonists. Compound 3-[2-(5-methyl-2H-tetrazol-2-yl)-3-(octadecylcarbamoyloxy) propylaminosulfonyl]propylquinolinium iodide (52) showed the most potent activity in the in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma (IC50 = 125 nM) and also in the in vivo protective effect on PAF-induced lethality in mice, with prolonged duration of action. Optically active enantiomers of this compound were synthesized and the (S)-(-)-isomer (IC50 = 87 nM) was found to be three times more potent that the (R)-(+)-isomer (IC50 = 289 nM), clearly exemplifying the enantioselectivity in the PAF-antagonist action of this novel compound.

Thromboxane A2 receptor antagonists. III. Synthesis and pharmacological activity of 6,6-dimethylbicyclo[3.1.1]heptane derivatives with a substituted sulfonylamino group at C-2.

Four stereoisomers of the title compounds based on side chain ring junctions, (+)-7a, (+)-7b, (-)-7c and (-)-24, were synthesized from (-)-myrtenol and (+)-nopinone. The (1R,2R,3S,5S)-isomer (+)-7b had the most potent inhibitory activity against platelet aggregation and did not show partial agonist activity (shape change of platelets). We also synthesized the antipode, (-)-7b, and derivatives of (+)-7b with various kinds of substituents at the sulfonylamino group, 34a-n and p. The one-carbon homologated compound, (+)-58, was also prepared. The inhibitory activities of these compounds against platelet aggregation were measured.

Thromboxane A2 receptor antagonists. II. Synthesis and pharmacological activity of 6,6-dimethylbicyclo[3.1.1]heptane derivatives with the benzenesulfonylamino group.

Various stereoisomers based on the alpha- and omega-side chain ring junctions of 6,6-dimethylbicyclo[3.1.1]heptane were synthesized. Their sodium salts 12, 18, 20, 30 and 37 were examined in vitro for their inhibitory activity toward aggregation of rabbit platelet-rich plasma and rat washed platelets. Their potency was very high and the partial agonist effect was small. The differences of the side chain ring junctions did not affect the activity very much. Homologation in the omega-side chain (as in 47) decreased the activity.

Thromboxane A2 receptor antagonists. I. Synthesis and pharmacological activity of 7-oxabicyclo-[2.2.1]heptane derivatives with the benzenesulfonylamino group.

Four stereoisomers of 7-oxabicyclo[2.2.1]heptane derivatives with the benzenesulfonylamino group, 11, 14, 23 and 33, were synthesized and their sodium salts were examined in vitro for inhibitory activity against aggregation of rabbit platelet-rich plasma and of rat washed platelets. The trans-isomer 23 exhibited high potency but showed a partial agonistic effect. Compound 11 did not show a partial agonistic effect, though it was a less active inhibitor. The following trans compounds were synthesized and their IC50 values were measured: homologated trans-isomers with one methylene chain (47 and 53), an olefin derivative (58), and optically active derivatives [-)-11 and (+)-23).