HQL 79

Pharmacological studies on the novel antiallergic drug HQL-79: II. Elucidation of mechanisms for antiallergic and antiasthmatic effects.[Pubmed:9804057]

Jpn J Pharmacol. 1998 Sep;78(1):11-22.

The effects of 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL-79), a newly developed antiallergic drug, on various chemical mediators and on chemical mediator release were investigated. Orally administered HQL-79 strongly inhibited the histamine-induced skin reaction in rats, and histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in guinea pigs. HQL-79 inhibited antigen-induced release of leukotriene (LT) B4, LTC4, histamine and prostaglandin (PG) D2 from the chopped lung tissues of actively sensitized guinea pigs. On the other hand, release of PGE2, one of the bronchoprotective prostanoids, was significantly enhanced by HQL-79. In an in vivo experiment, chronic administration of HQL-79 clearly reduced PGD2 contents and enhanced PGE2 contents in the lungs of repeatedly antigen-exposed guinea pigs. In biochemical studies, HQL-79 inhibited mouse spleen PGD synthase in a concentration-dependent manner. None of the antiallergics such as epinastine, terfenadine, oxatomide and cetirizine inhibited the PGD synthase. HQL-79 did not affect PGE synthase in sheep vesicular gland microsomes. These results suggest that antiallergic and antiasthmatic effects of HQL-79 could be ascribed to antihistaminic- and anti-5-HT effects, chemical mediator release inhibition, PGE2-release enhancement and PGD synthase inhibition. It is considered, in particular, that the differential modulation of PGD2 and PGE2 production is a conspicuous pharmacological feature of HQL-79.

Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase.[Pubmed:16547010]

J Biol Chem. 2006 Jun 2;281(22):15277-86.

We determined the crystal structure of human hematopoietic prostaglandin (PG) D synthase (H-PGDS) as the quaternary complex with glutathione (GSH), Mg2+, and an inhibitor, HQL-79, having anti-inflammatory activities in vivo, at a 1.45-A resolution. In the quaternary complex, HQL-79 was found to reside within the catalytic cleft between Trp104 and GSH. HQL-79 was stabilized by interaction of a phenyl ring of its diphenyl group with Trp104 and by its piperidine group with GSH and Arg14 through water molecules, which form a network with hydrogen bonding and salt bridges linked to Mg2+. HQL-79 inhibited human H-PGDS competitively against the substrate PGH2 and non-competitively against GSH with Ki of 5 and 3 microm, respectively. Surface plasmon resonance analysis revealed that HQL-79 bound to H-PGDS with an affinity that was 12-fold higher in the presence of GSH and Mg2+ (Kd, 0.8 microm) than in their absence. Mutational studies revealed that Arg14 was important for the Mg2+-mediated increase in the binding affinity of H-PGDS for HQL-79, and that Trp104, Lys112, and Lys198 were important for maintaining the HQL-binding pocket. HQL-79 selectively inhibited PGD2 production by H-PGDS-expressing human megakaryocytes and rat mastocytoma cells with an IC50 value of about 100 microm but only marginally affected the production of other prostanoids, suggesting the tight functional engagement between H-PGDS and cyclooxygenase. Orally administered HQL-79 (30 mg/kg body weight) inhibited antigen-induced production of PGD2, without affecting the production of PGE2 and PGF2alpha, and ameliorated airway inflammation in wild-type and human H-PGDS-overexpressing mice. Knowledge about this structure of quaternary complex is useful for understanding the inhibitory mechanism of HQL-79 and should accelerate the structure-based development of novel anti-inflammatory drugs that inhibit PGD2 production specifically.

Pharmacological studies on the novel antiallergic drug HQL-79: I. Antiallergic and antiasthmatic effects in various experimental models.[Pubmed:9804056]

Jpn J Pharmacol. 1998 Sep;78(1):1-10.

The effects of oral administration of 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL-79), a newly synthesized antiallergic drug, in various experimental allergic and asthmatic models were investigated. HQL-79 markedly inhibited immediate hypersensitivity reactions such as passive cutaneous anaphylaxis in rats, antigen-induced bronchoconstriction and nasal vascular permeability in actively sensitized guinea pigs, like epinastine and ketotifen did. Airway eosinophilia in repeatedly antigen-exposed guinea pigs was suppressed by chronic administration of HQL-79 for 2 weeks. In another experiment, the antigen-induced late asthmatic response (LAR) in metyrapone-treated guinea pigs was also ameliorated by chronic treatment with HQL-79. Moreover, HQL-79 partially inhibited the toluene diisocyanate-induced delayed-type hypersensitivity (DTH) reaction in mice when administered chronically during the immunization period. The corticosteroid dexamethasone inhibited the airway inflammatory responses in guinea pigs and the DTH in mice. These results indicate that HQL-79 has potent inhibitory effects on the immediate hypersensitivity reactions, and when administered chronically, it also inhibits airway eosinophilia, LAR and DTH, similarly to corticosteroids.

Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher.[Pubmed:16624958]

J Neurosci. 2006 Apr 19;26(16):4383-93.

Prostaglandin (PG) D2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD2 involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuroinflammation, including that which occurs during demyelination. Using the genetic demyelination mouse twitcher, a model of human Krabbe's disease, we discovered that activated microglia expressed HPGDS and activated astrocytes expressed the DP1 receptor for PGD2 in the brain of these mice. Cultured microglia actively produced PGD2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD2 receptor, DP1 and DP2, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD2 plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD2/DP signaling pathway using HPGDS- or DP1-null twitcher mice, and twitcher mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine), resulted in remarkable suppression of astrogliosis and demyelination, as well as a reduction in twitching and spasticity. Furthermore, we found that the degree of oligodendroglial apoptosis was also reduced in HPGDS-null and HQL-79-treated twitcher mice. These results suggest that PGD2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.

HQL-79 is a potent, selective and orally active human hematopoietic prostaglandin D synthase (H-PGDS) inhibitor, highly selectively inhibits the synthesis of PGD2, and acts as an anti-allergic agent, with a Kd of 0.8 μM and an IC50 of 6 μM. Shows no obvious effect on COX-1, COX-2, m-PGES, or L-PGDS.

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