Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis

Peter G Ruminski; Mark Massa; Joseph Strohbach; Cathleen E Hanau; Michelle Schmidt; Jeffrey A Scholten; Theresa R Fletcher; Bruce C Hamper; Jeffery N Carroll; Huey S Shieh; Nicole Caspers; Brandon Collins; Margaret Grapperhaus; Katherine E Palmquist; Joe Collins; John E Baldus; Jeffrey Hitchcock; H Peter Kleine; Michael D Rogers; Joseph McDonald; Grace E Munie; Dean M Messing; Silvia Portolan; Laurence O Whiteley; Teresa Sunyer; Mark E Schnute

doi:10.1021/acs.jmedchem.5b01434

Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis

J Med Chem. 2016 Jan 14;59(1):313-27. doi: 10.1021/acs.jmedchem.5b01434. Epub 2015 Dec 24.

Affiliations

¹ Pharmacokinetics, Dynamics, and Metabolism, Pfizer , 700 North Main Street, Cambridge, Massachusetts 02139, United States.
² Drug Safety, Pfizer , 1 Burtt Road, Andover, Massachusetts 01810, United States.

PMID: 26653735
DOI: 10.1021/acs.jmedchem.5b01434

Abstract

Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.

MeSH terms

Animals
Cartilage, Articular / drug effects
Cartilage, Articular / pathology
Collagenases / drug effects
Dogs
Drug Design
Humans
Kidney / metabolism
Macaca fascicularis
Male
Matrix Metalloproteinase 13 / drug effects*
Matrix Metalloproteinase Inhibitors / chemical synthesis*
Matrix Metalloproteinase Inhibitors / pharmacology*
Matrix Metalloproteinase Inhibitors / toxicity
Models, Molecular
Organic Anion Transporters, Sodium-Independent / metabolism
Osteoarthritis / drug therapy*
Protein Binding
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tetrazoles / chemical synthesis*
Tetrazoles / pharmacology*

Substances

Matrix Metalloproteinase Inhibitors
Organic Anion Transporters, Sodium-Independent
PF152 compound
Pyrimidines
Tetrazoles
organic anion transport protein 3
Collagenases
Matrix Metalloproteinase 13