Abstract
INS37217 [P1-(uridine 5′)-P4-(2′-deoxycytidine 5′)tetraphosphate, tetrasodium salt] is a deoxycytidine-uridine dinucleotide with agonist activity at the P2Y2 receptor. In primate lung tissues, the P2Y2 receptor mRNA was located by in situ hybridization predominantly in epithelial cells and not in smooth muscle or stromal tissue. The pharmacologic profile of INS37217 parallels that of UTP, leading to increased chloride and water secretion, increased cilia beat frequency, and increased mucin release. The combined effect of these actions was confirmed in an animal model of tracheal mucus velocity that showed that a single administration of INS37217 significantly enhanced mucus transport for at least 8 h after dosing. This extended duration of action is consistent with the ability of INS37217 to resist metabolism by airway cells and sputum enzymes. The enhanced metabolic stability and resultant increased duration of improved mucociliary clearance may confer significant advantages to INS37217 over other P2Y2 agonists in the treatment of diseases such as cystic fibrosis.
Footnotes
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Source of financial support: Inspire Pharmaceuticals, Inc. Portions of this report were presented at the 12th Biennial Congress of the International Society for Aerosols in Medicine, Vienna, Austria, June 12–16, 1999. Dougherty RW, Pendergast W, Yerxa BR, Evans RM, Sabater JR, Lopez JA, Abraham WM, Picher M, and Boucher RC (1999) INS542 and INS37217: novel P2Y2 receptor agonists with enhanced biological stability induce prolonged stimulation of tracheal mucus velocity in vivo (Abstract 196). J Aerosol Med12:141. Other portions were presented at the 14th Annual North American Cystic Fibrosis Conference, Baltimore, MD, November 9–12, 2000. Dougherty RW, Pendergast W, Sims I, Redick CC, Lang-Furr M, and Stutts MJ (2000) Effects of INS37217 on activation of recombinant human P2Y receptors and chloride secretion by dog tracheal epithelium (Abstract 257). Pediatr Pulmonol Suppl20:245; Dougherty RW, Pendergast W, Abraham WM, Sabater JR, and Davis CW (2000) Effects of P2Y2 receptor agonists on cilia beat frequency in cultured human airway epithelia and on tracheal mucus velocity (TMV) in sheep (Abstract 258). Pediatr Pulmonol Suppl20:245.
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DOI: 10.1124/jpet.102.035485
- Abbreviations:
- CF
- cystic fibrosis
- CFTR
- CF transmembrane regulator
- TMV
- tracheal mucus velocity
- INS365
- P1,P4-di(uridine 5′-)tetraphosphate, tetrasodium salt
- INS37217
- P1-(uridine 5′)-P4-(2′-deoxycytidine-5′)tetraphosphate, tetrasodium salt
- HPLC
- high-pressure liquid chromatography
- DMEM
- Dulbecco's modified Eagle's medium
- ISH
- in situ hybridization
- PCR
- polymerase chain reaction
- IVT
- in vitro transcription
- DNase
- deoxyribonuclease
- Isc
- short circuit current
- BEGM
- bronchial epithelial growth medium
- ALI
- air/liquid interface
- CBF
- ciliary beat frequency
- LHC
- Laboratory of Carcinogenesis
- Received February 27, 2002.
- Accepted April 24, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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