Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors

Brian A McKittrick; John P Caldwell; Thomas Bara; George Boykow; Madhu Chintala; John Clader; Michael Czarniecki; Brandy Courneya; Ruth Duffy; Linda Fleming; Rachel Giessert; William J Greenlee; Charles Heap; Liwu Hong; Ying Huang; Ulrich Iserloh; Hubert Josien; Tanweer Khan; Walter Korfmacher; Xian Liang; Robert Mazzola; Soumya Mitra; Kristina Moore; Peter Orth; Murali Rajagopalan; Sudipta Roy; Samuel Sakwa; Corey Strickland; Henry Vaccaro; Johannes Voigt; Hongwu Wang; Jesse Wong; Rumin Zhang; Andrew Zych

doi:10.1016/j.bmcl.2015.02.003

Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1592-6. doi: 10.1016/j.bmcl.2015.02.003. Epub 2015 Feb 10.

Authors

Brian A McKittrick¹, John P Caldwell², Thomas Bara³, George Boykow⁴, Madhu Chintala⁴, John Clader³, Michael Czarniecki³, Brandy Courneya⁵, Ruth Duffy⁴, Linda Fleming⁵, Rachel Giessert⁵, William J Greenlee³, Charles Heap⁵, Liwu Hong³, Ying Huang³, Ulrich Iserloh³, Hubert Josien³, Tanweer Khan³, Walter Korfmacher⁶, Xian Liang³, Robert Mazzola³, Soumya Mitra⁵, Kristina Moore⁴, Peter Orth⁷, Murali Rajagopalan³, Sudipta Roy⁵, Samuel Sakwa⁵, Corey Strickland⁷, Henry Vaccaro³, Johannes Voigt⁷, Hongwu Wang⁷, Jesse Wong³, Rumin Zhang⁸, Andrew Zych⁵

Affiliations

¹ Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: [email protected].
² Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: [email protected].
³ Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
⁴ Cardiovascular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
⁵ Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
⁶ Pharmacokinetics Pharmacodynamics and Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
⁷ Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
⁸ Biochemistry and Biophysics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.

PMID: 25728416
DOI: 10.1016/j.bmcl.2015.02.003

Abstract

The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

Keywords: BACE1; Enzyme inhibitors; Hypertension; Renin inhibitors; Structure-based drug design.

MeSH terms

Administration, Oral
Dose-Response Relationship, Drug
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Imines / chemical synthesis
Imines / chemistry
Imines / pharmacology*
Models, Molecular
Molecular Structure
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Renin / antagonists & inhibitors*
Renin / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Imines
Pyrimidinones
Renin