Angiotensin II AT2 receptor ligands with phenylthiazole scaffolds

• Published in: Bioorganic & medicinal chemistry Vol. 65; p. 116790
• Main Authors: Gopalan, Greeshma, Palo-Nieto, Carlos, Petersen, Nadia N., Hallberg, Mathias, Larhed, Mats
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.07.2022; Elsevier
• Subjects: Angiotensin II - chemistry; Angiotensin II - pharmacology; Angiotensin II type 2 receptor; Animals; AT1R selectivity; AT2R; ATR; ATR selectivity; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CYP enzyme inhibition; Engineering Science with specialization in Nanotechnology and Functional Materials; Humans; Imidazoles; Life Sciences & Biomedicine; Ligands; Liver microsomes; Mice; Pharmacology & Pharmacy; Phenylthiazole scaffolds; Physical Sciences; Rats; Receptor, Angiotensin, Type 2 - agonists; Receptors, Angiotensin; Science & Technology; Sulfonamides; Teknisk fysik med inriktning mot nanoteknologi och funktionella material; Thiophenes; Liver microsomes; AT1R selectivity; Angiotensin II type 2 receptor; AT2R; Phenylthiazole scaffolds; CYP enzyme inhibition; MIMICS; L-162,313; ATR selectivity; AGONISTS; AT; AFFINITY; CHEMISTRY; NONPEPTIDE; ATR
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2022.116790

[Display omitted] 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.