This article reviews the mechanisms and potential therapeutic uses of compounds with inhibitory effects on leukotriene B4 (LTB4) production or its activity, and focuses on compounds that have been shown in animal and/or human studies to have potential efficacy in treating dermatological disorders. These compounds, many of which are not familiar to many dermatologists, include inhibitors of 5-lipoxygenase such as ETH615, 15-hydroxyeicosatetraenoic acid, leflunomide, linetastine, lonapalene, MK886, R-68151 and zileuton, and antagonists of LTB4 such as SC53228, SC50605, SC51146 and VML295. The purpose of this paper is to introduce our colleagues to these potentially useful compounds currently in preclinical or early clinical testing.

01 Nov 1995·American Journal of Respiratory and Critical Care MedicineQ1 · MEDICINE

Effect of a leukotriene B4 receptor antagonist SC-53228 on ozone-induced airway hyperresponsiveness and inflammation in dogs.

Q1 · MEDICINE

Article

Author: Smith, W ; Vanderheyden, C ; Lane, C G ; Stevens, W H ; O'Byrne, P M ; Wattie, J

The importance of the potent neutrophil chemoattractant leukotriene (LT)B4 in causing ozone-induced bronchoconstriction, airway inflammation, and airway hyperresponsiveness in dogs was studied using the LTB4-receptor antagonist SC-53228. Seven dogs from random sources were studied three times, at least 2 wk apart. On each occasion, acetylcholine (Ach) airway responsiveness was measured before and 1 h after ozone (3 ppm, 30 min) or dry air inhalation, followed by a bronchoalveolar lavage (BAL). On the first day, dogs were treated with SC-53228 (0.4 mg/kg intravenously) followed by a continuous intravenous infusion of 1.2 mg/kg/h before ozone inhalation. On the other two days, diluent was infused followed by ozone or dry air inhalation. Cell counts were measured in BAL and cell activation was measured by spontaneous and by phorbol myristate acetate-stimulated (PMA) (2.4 mumol/L) oxygen radical release, measured from washed BAL cells (4 x 10(6) cells) by lucigenin-enhanced chemiluminescence. Ozone inhalation caused bronchoconstriction and airway hyperresponsiveness. SC-53228 inhibited the ozone-induced airway hyperresponsiveness (p = 0.006), but not the bronchoconstriction. Spontaneous (p = 0.004) and PMA-stimulated (p = 0.04) lucigenin-enhanced chemiluminescence were increased after ozone inhalation. The ozone-induced increases in PMA-stimulated chemiluminescence were significantly attenuated by treatment with SC-53228 (p = 0.04). These results suggest that LTB4 is involved in the pathogenesis of ozone-induced airway hyperresponsiveness, possibly through activation of airway inflammatory cell.

01 Nov 1995·GutQ1 · MEDICINE

Oral efficacy of a leukotriene B4 receptor antagonist in colitic cotton-top tamarins.

Q1 · MEDICINE

Article

Author: Smith, P ; Tanner, J ; Clapp, N ; Fretland, D ; Sanderson, T ; Fuhr, J ; Carson, R ; Adams, L

Leukotriene B4 (LTB4) is a potent neutrophil activator and chemotaxin that is present in increased concentrations in the colonic tissue and rectal dialysates of acute ulcerative colitis patients. Cotton-top tamarins (CTTs) with confirmed active colitis were treated with the second generation LTB4 receptor antagonist, SC-53228 ((+)-(S)-7-[3-(2-cyclopropyl-methyl)-3-methoxy-4-[(methylamino) carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- propanoic acid), 20 mg/kg bodyweight by gavage, twice daily for 56 days. End points were body weights, stool consistency, colonic endoscopy, assay of inflammatory mediators, and haematology and clinical chemistry tests. LTB4 and prostaglandin E (PGE) values were measured in rectal dialysates at pretreatment, 28 day and 56 day time points. LTB4 concentrations were reduced from pretreatment mean (SEM) values of 37.3 (0.8) ng/ml to 3.7 (0.8) ng/ml (p < 0.001) and 2.3 (0.5) ng/ml (p < 0.01) at days 28 and 56, respectively. On the other hand, mucosal protective PGE values remained constant or slightly increased during SC-53228 treatment (pre: 6.9 (2.2) ng/ml; day 28: 6.7 (1.4) ng/ml; day 56: 9.9 (1.6) ng/ml). Furthermore, assessment of a panel of 35 clinical chemistry and haematology parameters throughout the treatment showed there were no significant untoward effects of drug treatment. Six CCTs finished the eight week treatment and five of six gained weight (ranging from 27-121 grams each) while one CTT lost weight (50 g). Stool condition improved in five of six animals while one of six remained unchanged. All CCTs showed dramatic improvement histologically, with no or only minimally active colitis after treatment. The histological changes plus significant weight gains and improvement of stool condition (quality of life parameters) after eight weeks of SC-53228 treatment were remarkable. Furthermore, in follow up biopsies seven months after treatment ceased, three of six CTTs had no active colitis. This is the first time afflicted CTTs have not had recurring colitic exacerbations after a treatment regimen was stopped. It is concluded that in colitic CTTs, SC-53228 has shown both an immediate and a long acting anticolitic activity. It is also concluded that reduced LTB4 concentrations during treatment inhibited neutrophil infiltration of the colonic tissue and this, coupled with the maintenance of mucosal protective prostaglandins, contributed to the dramatic anticolitic efficacy. The treatment was safe over eight weeks. A compound such as SC-53228 may be useful in the medical treatment of human inflammatory bowel disease.

100 Deals associated with SC-53228

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Preclinical	US	Pharmacia Corp.	-
Colitis, Ulcerative	Preclinical	-	Pfizer Inc.	-
Colitis, Ulcerative	Preclinical	-	Pfizer Inc.	-
Colitis, Ulcerative	Preclinical	US	Pharmacia Corp.	-
Dermatitis	Preclinical	US	Pharmacia Corp.	-
Dermatitis	Preclinical	US	Pharmacia Corp.	-
Psoriasis	Preclinical	-	Pfizer Inc.	-
Psoriasis	Preclinical	US	Pharmacia Corp.	-
Psoriasis	Preclinical	US	Pharmacia Corp.	-
Psoriasis	Preclinical	-	Pfizer Inc.	-

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