Kaoru Seno

Characterization of a novel inhibitor of cytosolic phospholipase A2alpha, pyrrophenone.

Cytosolic phospholipase A(2)alpha (cPLA(2)alpha), one of the three subtypes of cPLA(2) (alpha, beta and gamma), is thought to be a rate-limiting enzyme in eicosanoid biosynthesis. We developed a novel and potent cPLA(2)alpha inhibitor with an optically active pyrrolidine, termed pyrrophenone, and characterized this compound in detail using enzyme and cellular assay systems. Pyrrophenone, which shows strong inhibition of cPLA(2)alpha activity, is one of the most potent cPLA(2)alpha inhibitors reported to date. Similar inhibitory potencies for cPLA(2)alpha were obtained from three different assays. The inhibitory activity of pyrrophenone is two or three orders of magnitude more potent than arachidonyl trifluoromethyl ketone (AACOCF(3)) under the same assay conditions. Pyrrophenone shows reversible inhibition of cPLA(2)alpha and displays no characteristics of the slow-binding inhibition observed for AACOCF(3). Pyrrophenone also inhibited the esterase and lysophospholipase activities of cPLA(2)alpha. However, the inhibition by pyrrophenone of 14 kDa secretory PLA(2)s, types IB and IIA, was over two orders of magnitude less potent than that for cPLA(2)alpha. Pyrrophenone strongly inhibited arachidonic acid release in calcium ionophore (A23187)-stimulated human monocytic cells (THP-1 cells) in a dose-dependent manner with an IC(50) value of 0.024 microM, followed by suppression of eicosanoid synthesis, and also showed dose-dependent inhibition for interleukin-1-induced prostaglandin E(2) synthesis in human renal mesangial cells with an IC(50) value of 0.0081 microM. The mechanism of inhibition of eicosanoid synthesis in these cell-based assays was due to inhibition of only one step of arachidonic acid release without any effect on cyclo-oxygenase or lipoxygenase pathways. These results suggest that pyrrophenone could be a potential therapeutic agent for inflammatory diseases.

Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2: synthesis of potent and crystallized 4-triphenylmethylthio derivative ‘Pyrrophenone’

We synthesized a potent and crystallized human cytosolic phospholipase A2alpha inhibitor, pyrrophenone (6) which inhibits the isolated enzyme with an IC50 value of 4.2 nM. Pyrrophenone shows potent inhibition of arachidonic acid release, prostaglandin E2, thromboxane B2, and leukotriene B4 formation in human whole blood. The magnitudes of prostaglandin E2 and thromboxane B2 inhibition are the same as those of indomethacin.

Monitored aminolysis of 3-acylthiazolidine-2-thione : A new convenient synthesis of amide

Abstract 3-Acylthiazolidine-2-thiones ( 1 ) were easily prepared and they were treated with several amines in dichloromethane to give amides 4 in very high yields within a short time. Aminoalcohols and aminophenols were selectively converted into acylaminoalcohols and acylaminophenols, respectively, by this reaction. One can monitor the reaction by disappearance of the yellow color of the starting material 1 . Some amide alkaloids ( 1 5 – 1 8 ) have effectively been synthesized.

Synthesis and chiroptical properties of bridged 2,2′-diaminobiphenyl derivatives

The relationship between c.d. spectra and the conformation of chiral 2,2′-diaminobiphenyls was investigated as a function of the torsion angle between the benzene ring planes. The molecular structures of (S)-(+)-4,5,6,7,11,12,13,14-octahydro[1]benzazocino[7,6,5-efg][1]benzazocine (22), (S)-(–)-2,2′-diamino-6,6′-dimethylbiphenyl (25), and (S)-(–)-(6R,7R)-5,6,7,8-tetrahydro-1,6,7,12-tetramethyldibenzo[e,g][1,4]diazocine (27) were determined by X-ray analysis. The shape of the c.d. spectrum of (22)(trans-conformation) is similar to those of (25) and (27)(cis-conformation). The experimental results and theoretical consideration by the exciton approximation and the π-SCF-MO approximation indicated that the shape of the c.d. spectrum is the same at least for torsion angles of 0–120°. On the other hand, the shape of the c.d. spectrum of the protonated species was inverted with a critical torsion angle of ca. 90°.

Total synthesis of a macrocyclic spermidine alkaloid, codonocarpine

Abstract Total synthesis of codonocarpine ( 5 ) and its regio-isomer ( 1 5 ) utilizing a new cyclization procedure is described.

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.

Design, synthesis, and pharmacological evaluation of dual histamine H2 and gastrin receptor antagonists

Abstract The joint type of hybrid molecules composed of two pharmacophore moieties taken from histamine H2 and gastrin receptor antagonists have been designed and synthesized to exhibit dual histamine H2 and gastrin receptor antagonistic activities. Here we report the importance of spacers as well as binding sites of both pharmacophores for the dual activity.

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 pharmacological evaluation of highly potent dual histamine H2 and gastrin receptor antagonists

Abstract The chemical modification of the dual histamine H2 and gastrin receptor antagonists described in our preceding paper, particularly the modification of spacers as well as the alteration of their connecting bonds at the gastrin receptor antagonist site (GA) from the amide bond to the carbamate bond, significantly improved not only their dual activity but also the GA versus CCK-A receptor selectivity.

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%.