2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists

2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A₃AR antagonists were discovered, including 3,5‐diphenyl[1,2,4]triazolo[4,3‐c]quinazoline ( 17 , K_i human A₃AR 1.16 nm ) and 5′‐phenyl‐1,2‐dihydro‐3′H‐spiro[indole‐3,2′‐[1,2,4]triazolo[1,5‐c]quinazolin]‐2‐one ( 20 , K_i human A₃AR 6.94 nm ). In addition, multitarget antagonists were obtained, such as the dual A₁/A₃ antagonist 2,5‐diphenyl[1,2,4]triazolo[1,5‐c]quinazoline ( 13 b , K_i human A₁AR 51.6 nm , human A₃AR 11.1 nm ), and the balanced pan‐AR antagonists 5‐(2‐thienyl)[1,2,4]triazolo[1,5‐c]quinazolin‐2‐amine ( 11 c , K_i human A₁AR 131 nm , A_2AAR 32.7 nm , A_2BAR 150 nm , A₃AR 47.5 nm ) and 9‐bromo‐5‐phenyl[1,2,4]triazolo[1,5‐c]quinazolin‐2‐amine ( 11 q , K_i human A₁AR 67.7 nm , A_2AAR 13.6 nm , A_2BAR 75.0 nm , A₃AR 703 nm ). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.     

Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands

Inhibition of adenosine A_2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A_2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A_2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A_2AR (K_i=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).     

Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4‐Dihydropyrazino[1,2‐b]indazol‐1(2H)‐one Derivatives

Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α₁) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2‐alkyl‐indazole‐amide derivatives. This study identified a 3,4‐dihydropyrazino[1,2‐b]indazol‐1(2H)‐one derivative with potent serotonin 2A receptor antagonism, >100‐fold selectivity over other serotonin subtype receptors, and high affinity for the α₁ receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol.