NO-Independent stimulators of soluble guanylate cyclase

doi:10.1016/S0960-894X(01)00073-7

Bioorganic & Medicinal Chemistry Letters

Volume 11, Issue 6, 26 March 2001, Pages 781-784

https://doi.org/10.1016/S0960-894X(01)00073-7 Get rights and content

Abstract

SARs around a novel type of guanylate cyclase stimulator which act by a mechanism different from classical NO-donors are described. Several pyrazolopyridinylpyrimidines are shown to relax aortic rings and revealed a long-lasting blood pressure lowering effect in rats after oral application.

The SARs around a novel type of stimulators of soluble guanylate cyclase, their relaxing effects on preconstricted rabbit aortic rings (measured as IC₅₀s) and their hypotensive properties are described.

Introduction

Soluble guanylate cyclase (sGC)¹ is a heterodimeric (α/β) heme-protein that converts GTP to cGMP, which is an important messenger in signal transduction. Its natural stimulator is nitric oxide, which stimulates sGC via the formation of a nitrosyl-heme complex. Organic nitrates like glycerol trinitrate or isosorbide dinitrate have been used for decades as a treatment for angina pectoris. In vivo they are converted to NO which relaxes vascular smooth muscles. The major drawback of this therapy is the development of tolerance after repeated applications. Recently an indazole derivative, YC-1, has been described, which stimulates sGC directly via a distinct mechanism and sensitizes the enzyme towards its native activator NO.² We used YC-1 as the lead structure and selected the pyrazolopyridine Bay 41-2272 (40) as the most promising one out of a series of thousands of newly synthesized derivatives.

Section snippets

Chemistry³

Pd-catalyzed biaryl-coupling is the method of choice for the preparation of indazole-derived compounds. However this route gives low yields when applied to compounds possessing more N-heteroatoms. Therefore, in the case of pyrazolopyridinyl-pyrimidines we applied an alternative sequence, for which a representative example is shown in Scheme 1.

Pharmacology⁴

For biological characterization we measured IC₅₀s for the ability of the compounds to inhibit maximum constriction of phenylephrine-treated preconstricted (3×10⁻⁸ g/mL) rabbit aortic rings. In order to prove the mechanism of relaxation, the stimulatory effect on isolated recombinant sGC alone and in the presence of NO was measured. The in vivo efficacy was shown in anaesthetized rats after oral administration.⁴

Results and discussion

We started the optimization process with the variation of the benzylic moiety of YC-1. At the methylene bridge no substitution like a carbonyl-oxygen or alkyl groups is tolerated. Omiting the methylene group with directly linked aromatics leads to inactive compounds. Table 1 reflects the influence of substituents at the aromatic part on the relaxation of preconstricted aortic rings. Fluorine proved to be preferable leading to compounds which show an increase in activity when changing the

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NO-Independent stimulators of soluble guanylate cyclase

Abstract

Introduction

Section snippets

Chemistry3

Pharmacology4

Results and discussion

Trends Pharmacol. Sci.

Pharmacol. Rev.

Angew. Chem., Int. Ed. Engl.

Angew. Chem., Int. Ed. Engl.

Angew. Chem., Int. Ed. Engl.

Blood

Br. J. Pharmacol.

EMBO J.

Br. J. Pharmacol.

Nitric Oxide

J. Mol. Med.

Chemistry³

Pharmacology⁴