L-162,389: a potent orally active angiotensin II receptor antagonist with balanced affinity to both AT1 and AT2 receptor subtypes

doi:10.1016/0960-894X(96)00017-0

Bioorganic & Medicinal Chemistry Letters

Volume 6, Issue 3, 6 February 1996, Pages 307-310

https://doi.org/10.1016/0960-894X(96)00017-0 Get rights and content

Abstract

Simple modifications made to our potent angiotensin II AT₁ selective clinical candidate MK-996 provided a compound with balanced binding affinity to both the AT₁ and the AT₂ receptor subtype. This compound, L-162,389, is orally active in rats and dogs.

Simple modifications made to our potent angiostensin II AT₁ selective clinical candidate MK-996 provided a compound with balanced binding affinity to both the AT₁ and AT₂ receptor subtype. This compound, L-162, 389, is orally active in rats and dogs.

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Cited by (8)

Angiotensin II AT2 receptor ligands with phenylthiazole scaffolds
2022, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Likewise, the structurally related isobutyl biphenyl derivative L-162,782 (2) acts as an AT1R agonist (Figure 1). Remarkably, a subtle alteration of structure of the latter agonist, i.e. removal of a methyl group from the side chain to provide the n–propyl biphenyl derivative L-162,389 (3) resulted in AT1R antagonism in vivo.3–4 The three ligands demonstrated essentially the same affinity to AT1R and AT2R.
The syntheses and the AT₁R and AT₂R binding data of a series of new small molecule ligands are reported. These ligands comprise a phenylthiazole scaffold rather than the biphenyl or phenylthiophene scaffolds found in essentially all of the previously described ligands originating from the nonselective AT₁R/AT₂R ligand L-162,313 and the AT₂R selective agonist C21, the latter now in Phase II/III clinical trials. A phenylthiazole rather than the phenylthiophene scaffold that is present in the AT₂R selective agonist C21 and in the AT₂R selective antagonist C38 had a deleterious effect on the affinity to AT₂R. Nevertheless, a significant improvement could be accomplished by introduction of a small bulky alkyl group in the 2-position of the imidazole ring attached through a methylene group bridge to the phenylthiazole scaffold. Hence, a combination of a 2-tert-butyl or a 2-isopropyl group and a butoxycarbonyl furnished potent AT₂R selective ligands. Furthermore, a high affinity ligand derived from L-162,313 and exhibiting a > 35 fold selectivity for AT₁R was identified (10). The ligand 21 with the 2-tert-butyl group and ∼ 35 fold selectivity for AT₂R, demonstrated high stability in human, rat and mouse liver microsomes and a very attractive profile with regard to the inhibition of common drug-metabolizing CYP enzymes. Thus, very low levels of inhibition of CYP 3A (5%), 2D6 (12%), 2C8 (26%), 2C9 (23%) and 2B6 (24%) were observed with the 2-tert-butyl derivative comprising the methoxycarbonyl sulfonamide function, levels that are significantly lower than those obtained with C21 under the same experimental conditions.
Discovery of Nonpeptide, Selective AT<inf>2</inf> Receptor Agonists
2015, The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications
This chapter summarizes the investigations on the structure–activity relationship of the first reported series of low-molecular-weight, selective, nonpeptide AT₂ receptor (AT₂R) agonists. The discussion herein includes the discovery processes of these drug-like AT₂R agonists that (a) started from nonselective AT₁/AT₂ receptor ligands and (b) started from stepwise conversion of the nonselective octapeptide angiotensin II. A pharmacophore model for the agonist series is presented, and some AT₂R antagonists, which are structurally related to the AT₂R agonists, are discussed. The AT₂R agonists provide valuable research tools when assessing the role of the AT₂R in vivo and can serve as important lead structures in drug discovery projects.
Angiotensin II receptor type 1 (AT<inf>1</inf>) selective nonpeptidic antagonists - A perspective
2010, Bioorganic and Medicinal Chemistry
Citation Excerpt :
The 5th position of terminal phenyl ring was explored and these compounds showed increased AT2 affinity. L-162,389 in which benzoyl sulfonamide acid group was replaced by n-butylsulfonylcarbamate having a propyl chain at the 5th position of the terminal phenyl showed increased AT2 antagonistic activity.192 Replacement of the acidic tetrazole functionality by various heterocyclic acid equivalents such as oxathiadiazole, thiatriazole and dioxobenzothiadiazine (120) were also tried.
Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT₁ and AT₂. Angiotensin II through AT₁ receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT₁) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT₁ antagonists are based on modifications of losartan structure, the first clinically used AT₁ antagonist. In this review, a comprehensive presentation of the literature on AT₁ receptor antagonists has been given.
Small-molecule AT2 receptor agonists
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2014, Journal of Molecular Modeling
Identifying structural features related to the biological activity of a series of AT1 antagonists from fragment-based drug design
2014, Protein and Peptide Letters

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L-162,389: a potent orally active angiotensin II receptor antagonist with balanced affinity to both AT1 and AT2 receptor subtypes

Abstract

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Com.

Trends Pharmacol. Sci.

Bioorg. & Med. Chem. Lett.

Bioorg. & Med. Chem. Lett.

Drugs

J. Med. Res. Rev.

Hypertension: Pathophysiology, Diagnosis and Management

J. Med. Chem.

J. Pharmacol. Exp. Ther.

L-162,389: a potent orally active angiotensin II receptor antagonist with balanced affinity to both AT₁ and AT₂ receptor subtypes