Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering

Abstract

A3 adenosine receptor (A3AR) ligands have been modified to optimize their interaction with the A3AR. Most of these modifications have been made to the N6 and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A3AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A3AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A3AR antagonists. Probably due to the “enigmatic” physiological role of A3AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A3AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.

Structure-Activity Analysis of Biased Agonism at the Human Adenosine A3 Receptor

“…The A 3 AR represents a novel therapeutic target for a number of pathologies (Jacobson and Gao, 2006;Fishman et al, 2012). Given their clinical potential, significant effort has been invested into identifying potent A 3 AR ligands with high subtype selectivity and minimal species variability (Jacobson et al, 2009;Müller and Jacobson, 2011). Currently, two A 3 AR agonists, N 6 -(3-iodobenzyl)adenosine-59-N-methyluronamide (IB-MECA) and 2-chloro-N 6 -(3-iodobenzyl)-adenosine-59-N-methyluronamide (Cl-IB-MECA), are in clinical trials for the treatment of psoriasis, rheumatoid arthritis, dry-eye syndrome, and hepatocellular carcinoma (Fishman et al, 2012).…”

“…The structure-activity relationship (SAR) of A 3 AR agonists has been investigated extensively (Jacobson et al, 2009). The affinity and/or subtype selectivity of A 3 AR agonists can be enhanced through substitution of the ribose tetrahydrofuryl group with a rigid bicyclo[3.1.0]hexane (methanocarba) ring system, the addition of m-substituted benzyl groups at the N 6 position, or the addition of alkyn-2-yl groups to the C2 position (Kim et al, 1994;Jacobson et al, 2000;Volpini et al, 2009;Tosh et al, 2012a).…”

Биологическая Активность Адамантансодержащих Моно- И Полициклических Пиримидиновых Производных (Обзор)

“…Ñîçäàíèå ñåëåêòèâíûõ ëèãàíäîâ äëÿ ñïåöèôè÷åñêèõ ðåöåïòîðîâ â íàñòîÿùåå âðåìÿ ïðèîáðåòàåò ïåðâîñòå-ïåííîå çíà÷åíèå [29,30]. Èçâåñòíî, íàïðèìåð, ÷òî àêòèâàöèÿ ðåöåïòîðîâ À 1 À è À 3 À ïðèâîäèò ê ñíèaeåíèþ óðîâ-íÿ öÀÌÔ, òîãäà êàê àêòèâàöèÿ ðåöåïòîðîâ À 2À À è À 2 À ñîïðîâîaeäàåòñÿ åãî óâåëè÷åíèåì.…”

Emerging treatment options for psoriasis

“…15 This receptor exerts its anti-inflammatory effects by inhibiting the proliferation of specific autoreactive T lymphocytes and downregulating the NF-κB signaling pathway, resulting in downregulation of proinflammatory cytokines and chemokines and in apoptosis of inflammatory cells. [16][17][18][19] In a Phase II study of CF101, an oral A3AR agonist, 35% of patients with moderate-to-severe plaque psoriasis receiving a 2 mg dose twice daily achieved at least 50% improvement in their Psoriasis Area and Severity Index (PASI) score at week 12. 16 Although this degree of efficacy seems to be less than that of methotrexate or biologics, improvement was significantly better in the treatment group when compared with placebo group in this study.…”