Human tryptase-beta (HTbeta) is a unique serine protease exhibiting a frame-like tetramer structure with four active sites directed toward a central pore. Potent inhibition of HTbeta has been attained using CRA-2059. This compound has two phenylguanidinium head groups connected via a linker capable of spanning between two active sites. The properties of the CRA-2059:HTbeta interaction were defined in this study. Tight-binding reversible inhibition was observed with an inhibition constant (Ki) of 620 pM, an association rate constant of 7x10(7) M(-1) s(-1) and a relatively slow dissociation rate constant of 0.04 s(-1). Bivalent inhibition was demonstrated by displacement of p-aminobenzamidine from the primary specificity pocket with a stoichiometry, [CRA-2059]0/[HTbeta]0, of 0.5. The potency of the bivalent interaction was illustrated by CRA-2059 inhibition of HTbeta, 24% or 53% inhibited by pre-incubation with an irreversible inhibitor. Two interactions were observed consistent with mono- and bi-valent binding; the Ki value for bivalent inhibition was at least 10(4)-fold lower than that for monovalent inhibition. Comparison of the affinities of CRA-2059 and phenylguanidine for HTbeta finds an approximate doubling of the free energy change upon bivalent binding. This doubling suggests that the linker portion minimally hinders the binding of CRA-2059 to HTbeta. The potency of CRA-2059 is thus attributable to effective bivalent binding.

01 Mar 2002·Alimentary Pharmacology & TherapeuticsQ1 · MEDICINE

Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open‐label pilot study

Q1 · MEDICINE

Article

Author: Wolf, D. C. ; Katz, J. A. ; Barish, Charles ; Safdi, Michael ; Salzberg, Bruce ; Koval, George ; Riff, Dennis ; Wolf, Douglas C. ; Katz, Jeffry A. ; Brzezinski, A. ; Gaspari, Michael ; Brzezinski, Aaron ; Kurth, M. C. ; Tremaine, William J. ; Tremaine, W. J. ; Fowler, Fred C. ; Fleming, T. J. ; Mordenti, J. ; Strenkoski-Nix, L. C.

Background:Mast cells isolated from the colonic mucosa in active ulcerative colitis appear to be partially degranulated, suggesting the release of tryptase.Aim:To investigate the safety and activity of APC 2059, a highly specific tryptase inhibitor, in the treatment of ulcerative colitis.Methods:This was an open‐label, Phase 2, multicentre pilot study in patients with mildly to moderately active ulcerative colitis, with a disease activity index of 6–9 on a 12‐point scale. Fifty‐six adults received 20 mg APC 2059 subcutaneously twice daily and 53 completed 28 days of treatment. The primary end‐point was response, defined as a final disease activity index of ≤ 3. Supplementary analyses were also performed.Results:Sixteen (29%) of 56 patients responded. Five (9%) showed complete remission (disease activity index=0). Twenty‐seven (49%) improved, with a final disease activity index of ≤ 3 or a four‐point reduction. Improvement or normalization in each category of the disease activity index was as follows: stool frequency, 64%; bleeding, 64%; endoscopy, 50%; physicians' rating, 63%. There were no significant relationships between outcome and pharmacokinetics. The most common adverse events were related to the injection site (32.1%).Conclusions:In this pilot study, the tryptase inhibitor APC 2059 was safe and there was evidence of activity in the treatment of ulcerative colitis.

01 Oct 2000·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Dibasic inhibitors of human mast cell tryptase. Part 2: Structure–activity relationships and requirements for potent activity

Q4 · MEDICINE

Article

Author: Lynne Cregar ; Kenneth D Rice ; Martin Wong ; William S Newcomb ; Wendy B Young ; Paul J Simpson ; Anthony R Gangloff ; Daun Putnam ; Jeffrey M Dener ; Elaine Y.-L Kuo ; Vivian R Wang

Detailed structure activity relationships (SARs) for a series of dibasic human tryptase inhibitors are presented. The structural requirements for potent inhibitory activity are remarkably broad with a range of core template modifications being well tolerated. Optimized inhibitors demonstrate potent anti-asthmatic activity in a sheep model of allergic asthma. APC-2059, a dibasic tryptase inhibitor with subnanomolar activity, has been advanced to phase II clinical trials for the treatment of both psoriasis and ulcerative colitis.

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	US	Celera Group	-
Colitis, Ulcerative	Phase 2	-	Bayer AG	-
Psoriasis	Phase 2	US	Celera Group	-

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