5-[6-1 -(Cyclohexyl-1 H-tetrazol-5-YL)hexyl]-1,8-naphthyridin-2-(1H)-one, SC-44368, a Potent Anti-aggregatory Agent which Selectively Inhibits Platelet Cyclic AMP Phosphodiesterase.

SC-44368 (5-[6-(1-cyclohexyl-1H-tetrazol-5-y)hexyl]-1,8-naphthyridin-2(1H)-one) is a potent and selective competitive inhibitor of platelet cyclic AMP-dependent phosphodiesterase (cAMP-PDE) (Ki: 1.65 µM). For the phosphodiesterase isoenzyms from human platelets SC-44368 shows a 26-fold selectivity (IC50 ratio) for the inhibition of the cAMP-PDE over the cyclic GMP-dependent phosphodiesterase (cGMP-PDE). By comparison, 3-isobutyl-1-methyl-xanthine (IBMX) inhibited the cAMP-PDE and cGMP-PDE from human platelets with approximately equal efficacy. Broad inhibitory activity was evident against human platelet aggregatory responses in vitro. IC50 values of 18.1 ± 5.3 µM (25 nM platelet activating factor, PAF), 17.3 ± 3.0 µM (1.0 µg/ml collagen) and 24.2 ± 10.3 µM (1µM ADP) were obtained against maximum increases in platelet-rich plasma (PRP) light transmission achieved by each agonist. SC-44368 potentiated the prostacyclin-induced increase of intra-platelet cAMP levels but did not potentiate the sodium nitroprusside-induced increase of intraplatelet cGMP levels. In an ex vivo model of platelet aggregation SC-44368 (3 mg/kg, i.v.) produced a potent inhibition of collagen-induced platelet aggregation. SC-44368 produced only weak hypotensive activity in the rat. Thus, SC-44368 is a novel cAMP-PDE inhibitor which possesses potent, broad spectrum anti-aggregatory properties.

A structurally novel inhibitor of cGMP phosphodiesterase with vasodilator activity.

A novel, potent, competitive inhibitor of smooth muscle cGMP phosphodiesterase is described (Compound I, [4-[2-n-butyl-5-chloro-1-(2- chlorobenzyl)imidazolyl]methyl] acetate). The compound is highly selective for inhibiting cGMP phosphodiesterase compared with cAMP phosphodiesterase. Compound I inhibits the contraction of smooth muscle in response to a variety of agonists in the same concentration range to that which inhibits the enzyme. Compound I produced a dose-related reduction in the pressor responses to angiotensin II infusion while not inhibiting the responses to bolus doses of angiotensin II. Two structural analogues of Compound I which did not inhibit cGMP phosphodiesterase failed to inhibit smooth muscle contraction in vitro and did not affect angiotensin II pressor responses in vivo. We propose a mechanism to account for the effects of a cGMP phosphodiesterase inhibitor on smooth muscle contraction in vitro and in vivo.

Immunoregulation in the common marmoset, Calithrix jaccus: functional properties of T and B lymphocytes and their response to human interleukins 2 and 4.

Non-human primates have been used to study immune function to a much lesser extent than readily available strains of inbred rodents. Nevertheless, in situations where it might be desirable, but impossible, to study human immune responses in vivo, lower primates could provide an acceptable alternative. In order to extent the knowledge of T- and B-lymphocyte function in lower primates, the common marmoset Callithrix jaccus was used as an experimental model. The functional similarities between this species and humans at the level of T-B co-operation in the antibody response were examined, and xenoreactive T-lymphocyte clones were obtained from marmoset spleen cells using Epstein-Barr virus (EBV)-transformed human B cells as stimulators. These clones could act as helper cells when co-cultured with human B lymphocytes, inducing the secretion of both IgM and IgG. Lymphokine production by mitogen-stimulated marmoset T-cell clones was also examined. Interleukins (IL) 2 and 4 activities were detected in clone supernatants using bioassays and interferon-gamma (IFN-gamma) was detected using a solid-phase ELISA system. However, SDS-PAGE analysis of biosynthetically labelled marmoset and human T-cell clone supernatant proteins revealed major differences between the soluble T-cell products of the two species. The proliferative responses of marmoset T and B cells to recombinant human IL-2 and IL-4 were also examined. Stimulation of [3H]thymidine uptake was detected in both T cell- and anti-IgM-stimulated B-cell cultures with both of the lymphokines. These results suggests that the key components of the antibody response are functionally conserved between lower primates and man and that the common marmoset may be useful as an in vivo model of immune function, particularly with regard to the role of interleukins such as IL-2 and IL-4.

Dibenzoquinazoline diones as antihypertensive cyclic guanosine monophosphate phosphodiesterase inhibitors.

The discovery and structure-activity of a new class of renal artery phosphodiesterase inhibitors is reported, some of which are highly selective for the guanosine cyclic 3',5'-monophosphate phosphodiesterase. One of these compounds, 5,6-dihydro-8,9,11,12-tetramethoxy-1,3-dioxo-1H-benz[f]- isoquino [8,1,2- hij]quinazoline-2(3H)-carboxylic acid, ethyl ester (9), is amongst the most potent and selective compounds of this class yet identified. Furthermore, this compound demonstrates an antihypertensive effect in vivo which is presumably mediated through vascular smooth muscle relaxation.