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Hartman, H.B., J.E. Roehr, B.L. Kotyuk, R.W. Kosley, Jr., R.J. Cherill, W.W. Petko, and P.G. Conway: HP 663: A novel compound for the treatment of glaucoma. Drug Dev. Res. 12:197-209, 1988. Various studies suggest that the 7-dihydroxypropionyl derivative of forskolin, HP 663, effectively lowers intraocular pressure (IOP) by a novel mechanism. Biochemically, HP 663 stimulates rat striatal adenylate cyclase and displays an affinity for forskolin binding sites similar to that of forskolin. Following topical administration this compound lowers IOP in both New Zealand White (NZW) and Dutch Belt (DB) rabbits. In NZW rabbits, concentrations from 0.05 to 2.0% in a buffered hydroxypropylmethylcellulose (HPMC) vehicle produce significant reductions in outflow pressures of 35-45% for 5-6 hr. Additionally, HP 663 is soluble in this vehicle up to a concentration of 0.25%. As mentioned, HP 663 also reduces IOP in DB rabbits; however, this response is not significant until a concentration of 1% is attained. The effect on aqueous humor inflow was indirectly determined by studying the rate of IOP recovery following rapid i.v. infusion of 20% NaCI. In NZW rabbits, HP 663 significantly reduced aqueous humor inflow as shown by a 40% decrease in the IOP recovery rate compared to control. Tolerance also does not appear to develop to the IOP lowering effects of HP 663 in NZW rabbits. This compound is still capable of significantly lowering IOP following twice daily treatment for 21 consecutive days. Following topical administration of concentrations which effectively lower IOP, HP 663 exhibits no significant effects on heart rate or blood pressure of NZW rabbits. Therefore, this compound does not appear to exhibit a potential for peripheral side effects after topical application. Based on the results of the present study, HP 663 appears to be a potent activator of adenylate cylase and may provide a novel and effective treatment for glaucoma.

S. Fielding: Vascular and cardiac effects of HP 406 and nifedipine in vitro and in conscious spontaneously hypertensive rats and renal hyptertensive dogs. Drug Dev. Res. 1517Res. -29, 1988.The cardiovascular effects of the calcium antagonists HP 406 and nifedipine were assessed in a series of in vitro and in vivo studies. HP 406 was found to display moderate affinity for dihydropyridine binding sites, as determined by the inhibition of [3H]-nitrendipine binding on rat ventricular membranes. HP 406 was found to have an IC50 of 1.3 x lo-' M as compared to nifedipine with an IC50 of 7.0 x lop9 M. Additional in vitro studies were conducted with isolated spontaneously contracting and electrically paced guinea pig atria and rabbit aortic rings. HP 406 was found to have minimal effects on cardiac chronotropic and inotropic activity in isolated guinea pig atria. In contrast, nifedipine caused significant dose-related reductions in heart rate and myocardial contractile force. Rabbit aortic rings were precontracted with potassium chloride (KCI) or norepinephrine (NE), and HP 406 or nifedipine was added to tissue baths in a cumulative dose range. HP 406 and nifedipine both caused dose-related relaxation of KCI-and NE-contracted rings; however, the IC5,,' s against KCI were found to be significantly lower than those against NE for both compounds.The lC50's against NE were found to be 4.8 x lo-* M and 5.9 x M for HP 406 and nifedipine, respectively. The lC5;s against NE were 1.9 x 1 0-5 M for HP 406 and 4.4 x