Current Pharmaceutical Design - Volume 7, Issue 3, 2001

Leukotriene A 4 (LTA4 ) hydrolase is a zinc containing enzyme which stereospecifically catalyzes the hydrolysis of the epoxide LTA 4 to the diol leukotriene B 4 (LTB4 ). There is substantial evidence that LTB 4 plays a significant role in the amplification of many inflammatory disease states. Therapeutic agents which selectively inhibit LTA4 hydrolase would block the formation of LTB4 and thus be potentially useful for the treatment of inflammation. Numerous inhibitors of LTA4 hydrolase have been reported over the past 15 20 years. Several early inhibitors were based on the structure of the natural substrate, LTA4 . Later approaches utilized known inhibitors of related zinc containing metalloproteinases and led to the identification of captopril, bestatin and kelatorphan as potent inhibitors of LTA4 hydrolase. This led to the design of a number of peptide and non peptide analogs which contained potential zinc chelating moieties, including thiols, hydroxamates and norstatines. A more recent series of non peptidic, non zinc chelating inhibitors of LTA4 hydrolase has been reported. This work led to the identification of several novel classes of analogs, including imidazopyridines, amidines and cyclic and acyclic amino acid derivatives, ultimately resulting in the identification of two potential clinical candidates SC 56938 and SC 57461A.

Recent progress in the development of inhibitors of human Type II s PLA2 as potential anti inflammatory agents is presented. While many companies have curtailed their efforts in the PLA2 area, Eli Lilly and Shionogi are continuing to advance LY 315920 (S 5920) as a potential treatment for sepsis and other diseases that have an inflammatory component. The Lilly developmental effort leading to LY 315920 is extensively reviewed, as well as the current status of other small molecular weight inhibitors of Type II s PLA2 that have been reported to be in late stage development.

Sub acute and chronic bronchitis (SACB) are among the least well studied major medical problems that exist today. While much research and novel drug discovery have focused on asthma, comparatively little has been performed on chronic bronchitis, the fourth or fifth most frequent disease (4 to 6 percent of the population over 45 years of age), or on sub acute bronchitis, the persistent symptoms of a respiratory infection which is the major reason Americans visit a physician (20 percent). This lack of attention is largely due to difficulties associated with modeling the pathophysiology of SACB in vitro, in situ, in organs or in animals as well as the presumption that drugs developed for asthma would also be effective in SACB. Data with bronchodilators (anti cholinergics versus beta 2 adrenergic agonist) and corticosteroids have strongly dismissed that premise. In this review of potential novel mechanistic targets directed specifically at SACB, an emphasis is given to recent data, gathered most convincingly from tissues and patients with cystic fibrosis, that have led to an appreciation of the critical role respiratory epithelial dysfunction plays in the pathophysiology and symptoms of these diseases. Mechanistic targets that restore (normalize or accelerate) airway cleansing (enhance host defense) by accelerating mucociliary clearance are described and given preference over anti inflammatory mechanisms that could further impair host defense.

Alopecia areata is considered to be a T cell mediated autoimmune disease of the hair follicle. Current immunosuppressive approaches and immunomodulatory treatment with contact sensitizers such as diphenylcyclopropenone and squaric acid dibutylester are dealt with in this review article. The efficacy of the various modes of treatment is evaluated by a review of literature and their mode of action is discussed. In accordance with the mechanism of autoimmune pathogenesis of AA, improved future treatments may be immunosuppressive or immunomodulatory, or they should otherwise protect the hair follicle from the injurious effects of the inflammation. Such possible future therapeutic approaches include the use of liposomes as an improved vehicle, application of immunosuppressive cytokines like TGF beta and IL 10, inhibition of apoptosis mediated by the Fas FasL system, inhibition of the lymphocyte homing receptor CD44v10, induction of tolerance as well as principles of gene therapy.