Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist

Jennifer X Qiao; Tammy C Wang; Réjean Ruel; Carl Thibeault; Alexandre L'Heureux; William A Schumacher; Steven A Spronk; Sheldon Hiebert; Gilles Bouthillier; John Lloyd; Zulan Pi; Dora M Schnur; Lynn M Abell; Ji Hua; Laura A Price; Eddie Liu; Qimin Wu; Thomas E Steinbacher; Jeffrey S Bostwick; Ming Chang; Joanna Zheng; Qi Gao; Baoqing Ma; Patricia A McDonnell; Christine S Huang; Robert Rehfuss; Ruth R Wexler; Patrick Y S Lam

doi:10.1021/jm4013906

Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist

J Med Chem. 2013 Nov 27;56(22):9275-95. doi: 10.1021/jm4013906. Epub 2013 Nov 12.

Affiliation

¹ Research and Development, Bristol-Myers Squibb Company , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.

PMID: 24164581
DOI: 10.1021/jm4013906

Abstract

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.

MeSH terms

Animals
Biological Availability
Drug Design*
Humans
Indoles / chemistry
Models, Molecular
Molecular Conformation*
Phenylurea Compounds / chemistry
Phenylurea Compounds / metabolism
Phenylurea Compounds / pharmacokinetics*
Phenylurea Compounds / pharmacology*
Purinergic P2Y Receptor Antagonists / chemistry
Purinergic P2Y Receptor Antagonists / metabolism
Purinergic P2Y Receptor Antagonists / pharmacokinetics*
Purinergic P2Y Receptor Antagonists / pharmacology*
Rats
Rats, Sprague-Dawley
Receptors, Purinergic P2Y1 / chemistry
Receptors, Purinergic P2Y1 / metabolism*
Sequence Homology, Amino Acid
Spiro Compounds / chemistry
Spiro Compounds / metabolism
Spiro Compounds / pharmacokinetics*
Spiro Compounds / pharmacology*
Urea / chemistry
Urea / metabolism
Urea / pharmacokinetics*
Urea / pharmacology*

Substances

1-(2-(1'-neopentylspiro(indoline-3,4'-piperidine)-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea
Indoles
Phenylurea Compounds
Purinergic P2Y Receptor Antagonists
Receptors, Purinergic P2Y1
Spiro Compounds
indoline
Urea