Synthesis and Structure−Activity Relationships of 1-Arylmethyl-5-aryl-6-methyluracils as Potent Gonadotropin-Releasing Hormone Receptor Antagonists

Abstract

Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-a]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-a]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed herein. Introduction of a small methyl substituent at the beta-position of the N3 side-chain improved the GnRH binding potency by 5-10-fold. Introduction of a methyl group of (R)-configuration at the alpha-carbon of the N-3 side-chain gave a modest improvement in binding affinity over the unsubstituted ethylene analogues. This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor.

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

“…When the rotational freedom of the 5-(3-methoxy)phenyl group was restrained with the introduction of a 2-fluoro substituent a dramatic increase in binding affinity was obtained (37; K i ¼ 1.1 nM). 54 Furthermore, 37 was a highly potent functional antagonist with an IC 50 -value of 0.5 nM. The metabolic stability of these compounds was poor and therefore branched primary amines were introduced at the N-3 side chain.…”

“…Niida and co-workers 148 performed both an alanine and D-amino acid scan of KP-10 to identify important residues for GPR54 agonistic activity. It was shown that five amino acids (50)(51)(52)(53)(54) were important for receptor binding and activation. Incorporation of a basic group, for example, guanidine, and substitution of Phe with Trp resulted in the first significantly downsized peptide GPR54 agonist with similar potency as KP-10 (EC 50 ¼ 1.4 nM).…”

Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives

“…The reaction of lithium enolate 34 − (R = Me) with γ -chloroketones gave tetrahydrofuranylmethyl uracils (37); however, the yields were low (Scheme 17).…”

“…[33][34][35] The synthesis of complexes 80 was accomplished at room temperature under MW irradiation with good yields that were better than with conventional heating, 33,34 with shorter reactions times (days to hours) and allowing the reactions to be performed, in some cases, without solvent. The authors studied several oxidants 35 phenyl with OCH 3 , OH, OCF 3 , OPh, alkyl, 37,38,39 F, Cl, SCH 3 , OR and alkenyl groups as substituents 37,39 were used to obtain moderate to good product yields.…”

Anti-Cancer Pyrimidines in Diverse Scaffolds: A Review of Patent Literature

“…Pyrimidine ring is the building unit of DNA and RNA, due to which pyrimidine derivatives exhibit diverse pharmacological activities such as anticancer [2][3][4][5][6][7][8][9][10], antiviral [11][12][13] especially anti-HIV [14][15][16], antimalarial [17][18][19], antimicrobial [20,21] and anti-inflammatory [22,23]. They also exhibit activity against gonadotropin releasing hormone receptors and display herbicidal potential by inhibiting acetohydroxyacid synthase, a key enzyme in the biosynthesis of branched-chain amino acids [24][25][26].…”