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Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone.
J Med Chem. 2003 Aug 28; 46(18):3865-76.JM

Abstract

Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a K(i) value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (K(i) = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-A resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness.

Authors+Show Affiliations

Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12930148

Citation

Costanzo, Michael J., et al. "Potent, Small-molecule Inhibitors of Human Mast Cell Tryptase. Antiasthmatic Action of a Dipeptide-based Transition-state Analogue Containing a Benzothiazole Ketone." Journal of Medicinal Chemistry, vol. 46, no. 18, 2003, pp. 3865-76.
Costanzo MJ, Yabut SC, Almond HR, et al. Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone. J Med Chem. 2003;46(18):3865-76.
Costanzo, M. J., Yabut, S. C., Almond, H. R., Andrade-Gordon, P., Corcoran, T. W., De Garavilla, L., Kauffman, J. A., Abraham, W. M., Recacha, R., Chattopadhyay, D., & Maryanoff, B. E. (2003). Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone. Journal of Medicinal Chemistry, 46(18), 3865-76.
Costanzo MJ, et al. Potent, Small-molecule Inhibitors of Human Mast Cell Tryptase. Antiasthmatic Action of a Dipeptide-based Transition-state Analogue Containing a Benzothiazole Ketone. J Med Chem. 2003 Aug 28;46(18):3865-76. PubMed PMID: 12930148.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone. AU - Costanzo,Michael J, AU - Yabut,Stephen C, AU - Almond,Harold R,Jr AU - Andrade-Gordon,Patricia, AU - Corcoran,Thomas W, AU - De Garavilla,Lawrence, AU - Kauffman,Jack A, AU - Abraham,William M, AU - Recacha,Rosario, AU - Chattopadhyay,Debashish, AU - Maryanoff,Bruce E, PY - 2003/8/22/pubmed PY - 2003/9/17/medline PY - 2003/8/22/entrez SP - 3865 EP - 76 JF - Journal of medicinal chemistry JO - J Med Chem VL - 46 IS - 18 N2 - Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a K(i) value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (K(i) = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-A resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/12930148/Potent_small_molecule_inhibitors_of_human_mast_cell_tryptase__Antiasthmatic_action_of_a_dipeptide_based_transition_state_analogue_containing_a_benzothiazole_ketone_ L2 - https://doi.org/10.1021/jm030050p DB - PRIME DP - Unbound Medicine ER -