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Facile Preparation of 4-Substituted Quinazoline Derivatives
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Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.

Peter Ray1, Jane Wright, Julia Adam

  • 1Discovery Research, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, UK. p.ray@btinternet.com

Bioorganic & Medicinal Chemistry Letters
|January 22, 2011
PubMed
Summary

Researchers optimized ROCK inhibitors for cardiovascular diseases, developing lead compound 14A. This new inhibitor shows efficacy in hypertensive rats and offers potential for improved selectivity, advancing ROCK-targeted therapies.

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Area of Science:

  • Medicinal Chemistry
  • Cardiovascular Pharmacology
  • Drug Discovery

Background:

  • Rho kinase (ROCK) is a key target in cardiovascular diseases.
  • Existing ROCK inhibitors have limitations that require optimization.
  • Fragment-derived ATP-competitive inhibitors serve as a starting point for drug development.

Purpose of the Study:

  • To optimize fragment-derived ATP-competitive ROCK inhibitors (1 and 2) into a lead compound (14A).
  • To enhance ROCK-I potency while maintaining a favorable pharmacokinetic (PK) profile.
  • To evaluate the in vivo efficacy and selectivity of the optimized compound.

Main Methods:

  • Chemical synthesis and optimization of ROCK inhibitors.
  • Biochemical assays to determine ROCK-I and ROCK-II potency.
  • In vivo studies using the spontaneous hypertensive rat model.
  • Selectivity profiling against Protein Kinase A (PKA).

Main Results:

  • Lead compound 14A was successfully developed through structural optimization, notably by removing the aminoisoquinoline basic center.
  • Compound 14A demonstrated equipotency against both ROCK-I and ROCK-II.
  • 14A exhibited good in vivo efficacy in a spontaneous hypertensive rat model.
  • Further optimization showed potential for improved selectivity over PKA compared to hydroxy Fasudil 3.

Conclusions:

  • The optimization strategy successfully yielded lead compound 14A with improved properties.
  • Compound 14A represents a promising candidate for further development in treating cardiovascular diseases.
  • The study highlights the potential for fine-tuning ROCK inhibitors for enhanced efficacy and selectivity.