PDBsum entry 1eas

Hydrolase (serine protease)

PDB id: 1eas

Contents

Protein chain

240 a.a. *

Ligands

SO4 ×3

TFK

Metals

_NA

Waters ×124

* Residue conservation analysis

PDB id:

1eas

Name:

Hydrolase (serine protease)

Title:

Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, x-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin- 2-one trifluoromethyl ketones

Structure:

Porcine pancreatic elastase. Chain: a. Engineered: yes

Source:

Sus scrofa. Pig. Organism_taxid: 9823

Resolution:

1.80Å R-factor: 0.183

Authors:

C.Ceccarelli

Key ref:

P.R.Bernstein et al. (1994). Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones. J Med Chem, 37, 3313-3326. PubMed id: 7932559 DOI: 10.1021/jm00046a016

Date:

22-Nov-94 Release date: 07-Feb-95

Protein chain

P00772  (CELA1_PIG) -  Chymotrypsin-like elastase family member 1 from Sus scrofa

Seq: 266 a.a.

Struc: 240 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.21.36 - pancreatic elastase.
• Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage: Ala-|-Xaa.

DOI no: 10.1021/jm00046a016

J Med Chem 37:3313-3326 (1994)

PubMed id: 7932559

Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones.

P.R.Bernstein, D.Andisik, P.K.Bradley, C.B.Bryant, C.Ceccarelli, J.R.Damewood, R.Earley, P.D.Edwards, S.Feeney, B.C.Gomes.

ABSTRACT

A series of nonpeptidic inhibitors of human leukocyte elastase (HLE) is reported. These trifluoromethyl ketone-based inhibitors contain a 3-amino-6-phenylpyridone group as a central template. The effect of varying the N-3 substituent in these inhibitors on in vitro potency, physical properties, and oral activity in a hamster based, HLE-induced lung damage model is described. The variety of substituents at this position that have little effect on in vitro potency supports the idea that this region of the molecule does not interact strongly with the enzyme. One exception to this generality is 13k, which is substituted with a (4-acetamidophenyl)sulfonyl group. This compound has a K(i) of 0.7 nM and is, in vitro, the most potent inhibitor in the series. In contrast, variation of the N-3 substituent was found to have a dramatic effect on activity after oral administration. Several analogs, including the parent amine, 7, formamide, 2u, benzyl sulfamide, 13e, and benzyl sulfonamide, 13f, show significant activity when administered at an oral dose of 2.5 mg/kg. Support for the modeling-based design concepts was obtained through in vitro SAR results and X-ray crystallographic analysis of the complex between 13d and porcine pancreatic elastase (PPE), a closely related enzyme.