873841-00-0Relevant articles and documents
A2Badenosine receptor antagonists: Design, synthesis and biological evaluation of novel xanthine derivatives
Basu, Sujay,Barawkar, Dinesh A.,Ramdas, Vidya,Waman, Yogesh,Patel, Meena,Panmand, Anil,Kumar, Santosh,Thorat, Sachin,Bonagiri, Rajesh,Jadhav, Dilip,Mukhopadhyay, Partha,Prasad, Vandna,Reddy, B. Srinivasa,Goswami, Arnab,Chaturvedi, Sandhya,Menon, Suraj,Quraishi, Azfar,Ghosh, Indraneel,Dusange, Sushant,Paliwal, Shalini,Kulkarni, Abhay,Karande, Vikas,Thakre, Rhishikesh,Bedse, Gaurav,Rouduri, Sreekanth,Gundu, Jayasagar,Palle, Venkata P.,Chugh, Anita,Mookhtiar, Kasim A.
, p. 986 - 996 (2017/02/12)
A2BAdoR is a low affinity adenosine receptor that functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like?COPD and asthma. Several potent and selective
Design and synthesis of novel xanthine derivatives as potent and selective A2B adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases
Basu, Sujay,Barawkar, Dinesh A.,Ramdas, Vidya,Patel, Meena,Waman, Yogesh,Panmand, Anil,Kumar, Santosh,Thorat, Sachin,Naykodi, Minakshi,Goswami, Arnab,Reddy, B. Srinivasa,Prasad, Vandna,Chaturvedi, Sandhya,Quraishi, Azfar,Menon, Suraj,Paliwal, Shalini,Kulkarni, Abhay,Karande, Vikas,Ghosh, Indraneel,Mustafa, Syed,De, Siddhartha,Jain, Vaibhav,Banerjee, Ena Ray,Rouduri, Sreekanth R.,Palle, Venkata P.,Chugh, Anita,Mookhtiar, Kasim A.
, p. 218 - 229 (2017/04/19)
Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A2B adenosine receptor (A2BAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory cond
Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists
Elzein, Elfatih,Kalla, Rao,Li, Xiaofen,Perry, Thao,Parkhill, Eric,Palle, Venkata,Varkhedkar, Vaibahv,Gimbel, Art,Zeng, Dewan,Lustig, David,Leung, Kwan,Zablocki, Jeff
, p. 302 - 306 (2007/10/03)
A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)- xanthine derivatives as A2B-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A2B, A 1, A2A, and A3-AdoRs. 8-(1-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (Ki = 1 nM) and selectivity for the A2B-AdoR versus A1, A2A, and A 3-AdoRs (A1/A2B, A2A/A2B, and A3/A2B selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: High affinity and selective A2B adenosine receptor antagonists
Kalla, Rao V.,Elzein, Elfatih,Perry, Thao,Li, Xiaofen,Palle, Venkata,Varkhedkar, Vaibhav,Gimbel, Arthur,Maa, Tennig,Zeng, Dewan,Zablocki, Jeff
, p. 3682 - 3692 (2007/10/03)
Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A2B adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A2B AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A 2B AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (Ki = 9 nM) for the A2B AdoR, but it is only 2-fold selective versus the A1 AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A2B AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF3 at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A2B AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and 36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A2B AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A2B AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A2B AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (Ki = 1 nM) A2B AdoR antagonist with high selectivity (990-, 690-, and 1000-) for the human A1, A2A, and A3 AdoRs.
