1NC6

Potent, small molecule inhibitors of human mast cell tryptase. Anti-asthmatic action of a dipeptide-based transition state analogue containing benzothiazole ketone

Summary for 1NC6

• Entry DOI: 10.2210/pdb1nc6/pdb
• Descriptor: Trypsinogen, CALCIUM ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: protein-inhibitor complex, hydrolase
• Biological source: Bos taurus (cattle)
• Cellular location: Secreted, extracellular space: P00760
• Total number of polymer chains: 1
• Total formula weight: 23906.95

Authors

Costanzo, M.J.,Yabut, S.C.,Almond Jr., H.R.,Andrade-Gordon, P.,Corcoran, T.W.,de Garavilla, L.,Kauffman, J.A.,Abraham, W.M.,Recacha, R.,Chattopadhyay, D.,Maryanoff, B.E. (deposition date: 2002-12-04, release date: 2003-09-23, Last modification date: 2024-10-23)

Primary citation

Costanzo, M.J.,Yabut, S.C.,Almond Jr., H.R.,Andrade-Gordon, P.,Corcoran, T.W.,De Garavilla, L.,Kauffman, J.A.,Abraham, W.M.,Recacha, R.,Chattopadhyay, D.,Maryanoff, B.E.
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., 46:3865-3876, 2003

PubMed 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.

PubMed: 12930148
DOI: 10.1021/jm030050p

Experimental method

X-RAY DIFFRACTION (1.9 Å)