Discovery of a Novel A_2B Adenosine Receptor Antagonist as a Clinical Candidate for Chronic Inflammatory Airway Diseases

Abstract

Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( 3 and 4) which have high affinity and selectivity for the human adenosine A 2B receptors (hA(2B)-AdoR). Unfortunately, this class of compounds had poor pharmacokinetic properties. This prompted us to investigate the effect of differential alkyl substitution at the N-1 and N-3 positions ( N 1-R not equal to N 3-R) on A(2B)-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A(2B)-AdoR, as well as improving oral bioavailability. This effort has led to the discovery of compound 62, that displayed high affinity and selectivity for the hA(2B)-AdoR (K(i) = 22 nM). In addition, compound 62 showed high functional potency in inhibiting the accumulation of cyclic adenosine monophosphate induced by 5'- N-ethylcarboxamidoadenosine in HEK-A(2B)-AdoR and NIH3T3 cells with K(B) values of 6 and 2 nM, respectively. In a single ascending-dose phase I clinical study, compound 62 had no serious adverse events and was well tolerated.

A2B Receptor Ligands: Past, Present and Future Trends

“…Unfortunately, this class of compounds showed poor pharmacokinetic properties. Further studies about this scaffold, and in particular on the influence of differential alkyl substitution at the N1-and N3-positions on the A 2B affinity and selectivity [38], led to the first A 2B antagonist with a potential significant therapeutic value CVT-6883 (15). CVT-6883 displayed high affinity and selectivity for the A 2B AR relative to the other adenosine subtypes and a good pharmacokinetic profile in rats.…”

BAY60-6583 Acts as a Partial Agonist at Adenosine A2B Receptors

“…On the other hand, the blockade of A 2B ARs was also shown to lead to anti-inflammatory effects. Therefore, A 2B -selective antagonists were proposed as a novel approach for the management and treatment of asthma and chronic obstructive pulmonary disease (Kalla et al, 2006Elzein et al, 2008), intestinal inflammation (Kolachala et al, 2008;El-Tayeb et al, 2011), and inflammatory pain (Bilkei-Gorzo et al, 2008).…”

1-Alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: Development and Characterization of Adenosine A2B Receptor Antagonists and a New Radioligand with Subnanomolar Affinity and Subtype Specificity

“…26 Compound 5 is currently evaluated for cardiopulmonary disease in an ascending-dose phase I clinical study by CV Therapeutics, representing the first A 2B antagonist in clinical trials. 27 Thus, the asthmatic response to adenosine is likely to be mediated via A 2B AdoR, providing a firm basis for the development of A 2B antagonists as new antiasthmatic agents. 28 The A 2B AdoR antagonists 8-(p-bromophenyl)-1-propargylxanthine (PSB-50), 4-(1-butylxanthin-8-yl)benzoic acid (PSB-53), 8-(4-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenyl)-1-butylxanthine (PSB-55), and PSB-1115 (3) were tested among other subtype-selective AdoR antagonists for their analgesic potency in mice using the hot plate test.…”

“…Chart 1. A 2B Antagonists and their K i Values at AdoR Subtypes (h ) Human, r ) Rat) 9,27,[40][41][42][43][44][45][46][47] A recent study showed that A 2B AdoR knockout mice exhibit attenuated tumor growth and decreased levels of vascular endothelial growth factor (VEGF) in the tumors after inoculation with Lewis lung carcinoma when compared to wild-type mice, pointing at the involvement of A 2B AdoR activation in the neovascularization of tumors. The release of VEGF was increased by the nonselective agonist NECA but not by the A 2A -selective AdoR agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (CGS-21680), whereas a combination of NECA and the selective A 2B AdoR antagonist 5 did not show this effect, indicating that A 2B antagonists might have the potential to inhibit tumor vascularization.…”