Michael A. Bray

Retinoids are potent inhibitors of the generation of rat leukocyte leukotriene B4-like activity in vitro

Several retinoids (tretinoin, retinol, retinal, retinyl acetate, etretinate and RO 10-1670) were tested in vitro for their ability to inhibit the generation of the leukocyte chemotactic factor leukotriene B4 (LTB4) from calcium ionophore-stimulated rat PMN in vitro. LTB4 activity was measured in vitro via bioassay using rat PMN aggregation and chemokinesis. Tretinoin, retinol, RO 10-1670 and retinal were active inhibitors of LTB4 generation with ID50S (microM) of 0.55-1.5, 5.9-6.5, 4.8-5.9 and 19-28.4 respectively whilst retinyl acetate and etretinate were inactive. Inhibition of the generation of LTB4 by tretinoin was confirmed by reverse phase-high pressure liquid chromatography. These results are discussed in the context of retinoid treatment of skin diseases such as psoriasis where inhibition of neutrophil accumulation during retinoid treatment has been reported.

Synthesis and SAR of a novel, potent and structurally simple LTD4 antagonist of the quinoline class.

The two geminal ethyl groups in the succinic acid moiety of CGP57698 (4-[3-(7-fluoro-2-quinolinyl-methoxy)phenyl-amino]-2,2-diethyl-4-oxo- butanoic acid) are responsible for the high in vitro and in vivo potency of this peptidoleukotriene antagonist of the quinoline type. The synthesis and structure activity relationships of CGP57698 and its analogs are described.

CGP57698: A Structurally Simple, Highly Potent Peptidoleukotriene (PLT) Antagonist of the Quinoline Type

A number of peptido-leukotriene antagonists coming from a variety of different structural classes have been developed over the last ten years and are in clinical development as anti-asthmatic agents.1, 2, 3 Many of these compounds are complex molecules and we have aimed at developing novel compounds which combine structural simplicity with high oral potency. Compounds of the quinoline type were considered to be suitable target structures for the design of new potent and highly bioavailable LTD4 antagonists.4, 5 The clinically most advanced compound of this type is at present MK-0476 (montelukast sodium).6 The quinoline antagonists, characterized by a substituent in the 2 position consisting of a spacer with 2 atoms, an additional aromatic moiety and a terminal acidic group, show good in vitro and in vivo activity including ease of synthesis. The nature of this acidic residue is of key importance for the pLT antagonist potency of quinoline type antagonists. Combination of the required structural elements led to the synthesis of CGP57698 (4-[3-(7-fluoro-2-quinolinyl-methoxy)phenyl-amino]-2,2-diethyl-4-oxo-buta-noic acid). In CGP57698 the acidic group is derived from succinic acid with two geminal ethyl groups, which are essential for the high potency of CGP57698.

The development of iralukast: A member of the Novartis series of cysteinyl leukotriene antagonists

The development of specific antagonists of cysteinyl leukotrienes (Cys-LTs) has provided therapeutic agents for use in diseases of the respiratory tract by antagonizing the bronchoconstrictive, mucus secretory and inflammatory effects of these leukotrienes [1–8]. Pranlukast (OnonTM, ONO-1078), zafirlukast (AccolateTM, ICI 204,219) and montelukast (SingulairTM, MK 0476) are available on the market as treatment for asthma [1–6]. Further compounds, such as iralukast (CGP 45715A) are in development for this indication [7,8].