The arachidonic acid (AA) metabolic network produces key inflammatory mediators which have been considered as hallmark contributors in various inflammatory related diseases. Enzymes in this network, such as 5-lipoxygenase (5-LOX), cyclooxygenase (COX), leukotriene A(4) hydrolase (LTA4H) and prostaglandin E synthase (PGES), have been used as targets for anti-inflammatory drug discovery. Multi-target drugs and drug combinations have also been developed for this network. However, how the inhibitors alter the dynamics of metabolite production and which combinatorial target intervention solutions are better needs further exploration. We did a system based intervention analysis on the AA metabolic network. Using an LC-MS/MS method, we quantitatively studied the eicosanoid metabolites responses of AA metabolic network during stimulation of Sprague Dawley rat blood samples with the calcium ionophore. Our results indicate that inhibiting the upstream rather than the downstream target of 5-LOX pathway will simultaneously alter the AA metabolism to the COX pathway (and vice versa). Therefore, single-target inhibitors cannot control all the inflammatory mediators at the same time. We also suggest that in the case of multiple-target anti-inflammatory solutions, the combination of inhibitors of the downstream enzymes may have stronger inhibition efficiency and cause less side-effects compared to the other solutions. One therapeutic strategy, LTA4H/COX inhibition solution, was found promising for the intervention of inflammatory mediator biosynthesis and at the same time stimulating the production of anti-inflammatory agents.

01 Aug 2002·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis of Potent Leukotriene A₄ Hydrolase Inhibitors. Identification of 3-[Methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic Acid

Q1 · MEDICINE

Article

Author: Russell, Mark A. ; Kim, Suzanne H. ; Villani-Price, Doreen ; Liang, Chi-Dean ; Chen, Barbara B. ; Highkin, Maureen K. ; Yu, Stella S. ; Miyashiro, Julie M. ; Gierse, James K. ; Malecha, James W. ; Harding, Elizabeth I. ; Kachur, James F. ; Penning, Thomas D. ; Askonas, Leslie J. ; Chen, Helen Y. ; Ghoreishi-Haack, Nayereh S. ; Mahoney, Matthew W. ; Smith, Walter G. ; Pyla, E. Yvonne

Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.

01 Feb 2000·Journal of Medicinal ChemistryQ1 · MEDICINE

Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A₄ (LTA₄) Hydrolase

Q1 · MEDICINE

Article

Author: Gasiecki, Alan F. ; Highkin, Maureen K. ; Durley, Richard C. ; Kachur, James F. ; Yu, Stella S. ; Djuric, Stevan W. ; Kilpatrick, Brian F. ; Gierse, James K. ; Ghoreishi-Haack, Nayereh S. ; Parnas, Barry L. ; Docter, Stephen H. ; Chen, Barbara B. ; Askonas, Leslie J. ; Kim, Suzanne H. ; Miyashiro, Julie M. ; Russell, Mark A. ; Pyla, E. Yvonne ; Haack, Richard A. ; Smith, Walter G. ; Harding, Elizabeth I. ; Desai, Bipin N. ; Krivi, Gwen G. ; Villani-Price, Doreen ; Chandrakumar, Nizal S. ; Chen, Helen Y. ; Penning, Thomas D. ; Corley, David G.

Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammatory Bowel Diseases	Preclinical	United States	G.D. Searle & Co., Inc.	08 Feb 2000
Psoriasis	Preclinical	United States	G.D. Searle & Co., Inc.	08 Feb 2000

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