GS-5759, A Novel Bi-Functional Phosphodiesterase 4 Inhibitor And Long-Acting ²2-Adrenoceptor Agonist, In Vitro Pharmacology On Guinea Pig Tracheal Smooth Muscle Strips

Abstract

Rationale: GS-5759 is a bi-functional that is being phosphodiesterase 4 (PDE4) inhibitor and long-acting adrenoceptor agonist (LABA) developed as a novel therapy for chronic obstructive pulmonary disease (COPD). GS-5759 is a potent β -adrenoceptor agonist with low 2 We evaluated the nanomolar activity at cloned human β receptors.2 β agonist 2 pharmacology of GS-5759 at endogenous receptors in guinea pig tracheal smooth muscle with respect to potency, full agonism and association and disassociation kinetics. guinea pig tracheal strips stabilized in oxygenated Krebs buffer containing Methods & Results: Experiments were performed on indomethacin (10 μM) employing a DMT myograph system. The potency of GS-5759 was measured as percentage inhibition of carbachol (0.3 μM) -induced contraction and demonstrated a concentration-dependent inhibition with an IC of 257 nM compared to 356 nM for 50 indacaterol. Incubation of tissue strips with the β 2 receptor antagonist ICI-118551 (10 μM) completely abolished the contractile effects of GS-5759 (300 nM and 1 μM) did not inhibit the ability of isoproterenol (30 nM-10 μM) to mediate relaxation of GS-5759 (1 nM-10 μM). guinea pig tracheal airway smooth muscle, suggesting that it is a full agonist at β -adrenoceptors.2 GS-5759 demonstrated a time-and concentration-dependent relaxation of carbachol pre-contracted strips, at 3 μM the time to 50% association (On t ) was 10 ± 2 min 1/2 compared to indacaterol (3 μM) with an On t of 6 ± 0.3 min. The disassociation rate of GS-5759 was measured by monitoring the 1/2 recovery of functional carbachol-induced contraction following wash-out of compound from tissue baths. After 3h washout GS-5759 and indacaterol (both 300 nM) maintained >90% relaxation compared to t=0, and after 12 h wash-out they retained 60 ± 9% and 49 ± 9% relaxation respectively. These data suggest GS-5759 has a slow functional dissociation rate and are consistent with a long duration of effect at β receptors.2 Conclusion: GS-5759 is a potent, full β 2 -adrenoceptor agonist at endogenous β 2 receptors in guinea pig tracheal smooth muscle strips, with comparable potency to indacaterol. GS-5759 has concentration-dependent association kinetics and has a slow functional dissociation rate comparable to indacaterol. These data are consistent with GS-5759 being a long acting β 2 -adrenoceptor agonist which may have clinical utility in COPD. This abstract is funded by: Gilead Sciences Inc.