Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase

Michael N GRECO; Michael J HAWKINS; Angelene M CANTWELL; Savvas N SAVVIDES; Bruce P DAMIANO; Bruce E MARYANOFF; Eugene T POWELL; Harold R ALMOND; Lawrence DE GARAVILLA; Jeffrey HALL; Lisa K MINOR; YUANPING YUANPING WANG; Thomas W CORCORAN; Enrico DI CERA

doi:10.1021/jm0700619

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Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase

Journal article

Peer reviewed

Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase

Michael N GRECO, Michael J HAWKINS, Angelene M CANTWELL, Savvas N SAVVIDES, Bruce P DAMIANO, Bruce E MARYANOFF, Eugene T POWELL, Harold R ALMOND, Lawrence DE GARAVILLA, Jeffrey HALL, …

Journal of medicinal chemistry, Vol.50(8), pp.1727-1730

03/16/2007

DOI: https://doi.org/10.1021/jm0700619

PMID: 17361995

Abstract

Biological and medical sciences

Medical sciences

Pharmacology. Drug treatments

Bones, joints and connective tissue. Antiinflammatory agents

A series of β-carboxamido-phosphon(in)ic acids (2) was identified as a new structural motif for obtaining potent inhibitors of human mast cell chymase. For example, 1-naphthyl derivative 5f had an IC50 value of 29 nM and (E)-styryl derivative 6g had an IC50 value of 3.5 nM. An X-ray structure for 5f·chymase revealed key interactions within the enzyme active site. Compound 5f was selective for inhibiting chymase versus eight serine proteases. Compound 6h was orally bioavailable in rats (F = 39%), and orally efficacious in a hamster model of inflammation.

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Title: Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase
Creators: Michael N GRECO - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Michael J HAWKINS - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Angelene M CANTWELL - Department of Biochemistry and Molecular Biophysics, Washington University, School of Medicine, St. Louis, Missouri 63110, United States
Savvas N SAVVIDES - Department of Biochemistry and Molecular Biophysics, Washington University, School of Medicine, St. Louis, Missouri 63110, United States
Bruce P DAMIANO - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Bruce E MARYANOFF - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Eugene T POWELL - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Harold R ALMOND - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Lawrence DE GARAVILLA - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Jeffrey HALL - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Lisa K MINOR - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
YUANPING YUANPING WANG - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Thomas W CORCORAN - Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, United States
Enrico DI CERA - Department of Biochemistry and Molecular Biophysics, Washington University, School of Medicine, St. Louis, Missouri 63110, United States
Publication Details: Journal of medicinal chemistry, Vol.50(8), pp.1727-1730
Publisher: American Chemical Society; Washington, DC
Identifiers: 9923982486901921
Academic Unit: Department of Biology
Language: English
Resource Type: Journal article

Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase

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