| Reference | 1. ACS Med Chem Lett. 2019 Jul 15;10(8):1228-1233. doi:
10.1021/acsmedchemlett.9b00274. eCollection 2019 Aug 8.
<br>
Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient
Receptor Potential Vanilloid 4 (TRPV4).
<br>
Brooks CA(1), Barton LS(1), Behm DJ(1), Eidam HS(1), Fox RM(1), Hammond M(1),
Hoang TH(1), Holt DA(1), Hilfiker MA(1), Lawhorn BG(1), Patterson JR(1), Stoy
P(1), Roethke TJ(1), Ye G(1), Zhao S(1), Thorneloe KS(1), Goodman KB(1), Cheung
M(1).
<br>
Author information: <br>
(1)Heart Failure Discovery Performance Unit, GlaxoSmithKline, Metabolic Pathways
and Cardiovascular Therapeutic Area, 1250 South Collegeville Road, Collegeville,
Pennsylvania 19426, United States.
<br>
GSK2798745, a clinical candidate, was identified as an inhibitor of the transient
receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary
edema associated with congestive heart failure. We discuss the lead optimization
of this novel spirocarbamate series and specifically focus on our strategies and
solutions for achieving desirable potency, rat pharmacokinetics, and
physicochemical properties. We highlight the use of conformational bias to
deliver potency and optimization of volume of distribution and unbound clearance
to enable desirable in vivo mean residence times.
<br><br>
2. Am J Cardiovasc Drugs. 2019 Jun;19(3):335-342. doi: 10.1007/s40256-018-00320-6.
<br>
Clinical Pharmacokinetics, Safety, and Tolerability of a Novel, First-in-Class
TRPV4 Ion Channel Inhibitor, GSK2798745, in Healthy and Heart Failure Subjects.
<br>
Goyal N(1), Skrdla P(2), Schroyer R(2), Kumar S(3), Fernando D(3), Oughton A(2),
Norton N(3), Sprecher DL(2), Cheriyan J(3)(4).
<br>
Author information: <br>
(1)GlaxoSmithKline, UP4300 East, 1250 S College Road, Collegeville, PA, 19426,
USA. [email protected].
(2)GlaxoSmithKline, UP4300 East, 1250 S College Road, Collegeville, PA, 19426,
USA.
(3)GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke’s Hospital, Cambridge,
UK.
(4)Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
<br>
INTRODUCTION AND OBJECTIVE: Pulmonary capillary endothelial transient receptor
potential vanilloid 4 (TRPV4) channel plays a critical role in mediating the
development of cardiogenic pulmonary edema. GSK2798745 is a first-in-class,
highly potent, selective, orally active TRPV4 channel blocker being evaluated in
a first-time-in-humans study (NCT02119260).<br>
METHODS: GSK2798745 was administered in a randomized, placebo-controlled study
design to healthy volunteers in three separate cohorts as single escalating
doses, with and without food, and as once-daily repeat doses for up to 14 days,
respectively. Two cohorts of subjects with mild to moderate heart failure were
also administered GSK2798745 once daily for up to 7 days. Safety, tolerability,
and systemic exposure data were collected.<br>
RESULTS: No significant safety issues or serious adverse events were observed
with GSK2798745 in healthy volunteers and patients with heart failure. GSK2798745
systemic exposure data demonstrated linear pharmacokinetics up to 12.5 mg, less
than twofold accumulation with once-daily dosing, and a systemic half-life of
~ 13 h. There was a slight increase in GSK2798745 exposure [14% increase in area
under the plasma concentration-time curve (AUC) and 9% increase in maximum
observed plasma concentration (Cmax)] after administration with a high-fat meal.
CONCLUSIONS: GSK2798745 was well-tolerated in healthy volunteers and patients
with stable heart failure. The safety and exposure data obtained in this study
allow further evaluation of the drug in long-term clinical studies in heart
failure as well as other indications.<br>
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