Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2a agonist, in preclinical models q Achim H.P. Krauss a, * , Francesco Impagnatiello b , Carol B. Toris c , David C. Gale a , Ganesh Prasanna a , Valentina Borghi b , Valerio Chiroli b , Wesley K.M. Chong a , Samantha T. Carreiro a , Ennio Ongini b a Pfizer Inc, San Diego, CA, USA b NicOx Research Institute, Milan, Italy c University of Nebraska Medical Center, Omaha, NE, USA article info Article history: Received 19 November 2010 Accepted in revised form 2 March 2011 Available online 9 March 2011 Keywords: glaucoma prostaglandin nitric oxide IOP pharmacokinetics BOL-303259-X abstract The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prosta- glandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 mg) and 0.12% (36 mg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 mg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intra- vitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Glaucoma comprises a family of optic neuropathies which are the leading cause of preventable blindness in the world. Risk factors include elevated intraocular pressure (IOP), family history, age, African-American ethnicity and severe near- or far-sightedness (Rivera et al., 2008). Currently, the only treatable risk factor is high IOP. Prostaglandin F2alpha (PGF2a) agonist analogs, such as lata- noprost (Xalatan Ò ), are powerful ocular hypotensive agents with considerably fewer side effects in the eye compared to other PGF2a agonists (Camras and Bito, 1981; Camras et al., 1992; Camras, 1996; Stjernschantz et al., 1995) and thus they have become a mainstay in glaucoma therapy (Stewart et al., 2008). This class of agents exerts their IOP lowering activity through a mechanism mainly involving long-term remodeling of the extracellular matrices in the ciliary body thereby increasing uveoscleral aqueous humor outflow (Lütjen-Drecoll and Tamm,1988; Nilsson et al.,1989; Gabelt and Kaufman, 1989; Lindsey et al., 1997; Richter et al., 2003). Nitric oxide (NO), a mediator generated endogenously from L-arginine by a family of enzymes named NO synthases and signaling via the second messenger cGMP, has also been implicated in IOP homeostasis in primary open angle glaucoma (POAG) patients as well as in preclinical animal models of glaucoma. Nitrovasodilators including nitroglycerin, isosorbide dinitrate and hydralazine have been reported to lower IOP in primates and rabbits following topical administration (Nathanson, 1992; Schuman et al., 1994; Kotikoski et al., 2002). In the normal human eye, the aqueous humor outflow pathway and ciliary muscle are enriched sites of NO synthesis from q The compound which is now being developed by Bausch & Lomb Incorporated, Rochester, New York was originally identified with the code NCX 116 and later with PF-3187207. * Corresponding author. GlaxoSmithKline Ophthalmology, 2301 Renaissance Blvd, King of Prussia, PA, 19406, USA. Tel.: þ1 610 787 3364. E-mail address: achim.h.krauss@gsk.com (A.H.P. Krauss). Contents lists available at ScienceDirect Experimental Eye Research journal homepage: www.elsevier.com/locate/yexer 0014-4835/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.exer.2011.03.001 Experimental Eye Research 93 (2011) 250e255