Discovery of potent, selective, and orally bioavailable PDE5 inhibitor: Methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate (CKD 533)

Bioorg Med Chem Lett. 2010 Jan 1;20(1):383-6. doi: 10.1016/j.bmcl.2009.10.071. Epub 2009 Oct 21.

Abstract

In a continuing effort to discover novel PDE5 inhibitors, we have successfully found quinazolines with 4-benzylamino substitution as potent and selective PDE5 inhibitors. Initial lead compound (1) was found to be easily metabolized when incubated with human liver microsomes mainly through C6 amide hydrolysis. Blocking of this metabolic hot spot led to discovery of 10 (CKD533) which is highly potent, selective and orally efficacious in conscious rabbit model for erectile dysfunction and now is undergoing preclinical toxicology study.

MeSH terms

  • Administration, Oral
  • Animals
  • Carbamates / chemical synthesis
  • Carbamates / chemistry*
  • Carbamates / pharmacology
  • Catalytic Domain
  • Computer Simulation
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Erectile Dysfunction / drug therapy
  • Humans
  • Male
  • Microsomes, Liver / metabolism
  • Phosphodiesterase 5 Inhibitors*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology
  • Rabbits
  • Rats

Substances

  • Carbamates
  • Enzyme Inhibitors
  • Phosphodiesterase 5 Inhibitors
  • Quinazolines
  • methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate
  • Cyclic Nucleotide Phosphodiesterases, Type 5