ABSTRACT
GSK2798745, an antagonist of the transient receptor potential vanilloid 4 (TRPV4) ion channel, was recently investigated in clinical trials for the treatment of cardiac and respiratory diseases. Human plasma and urine samples collected from healthy volunteers following oral administration were analyzed to identify circulating and excreted metabolites of the parent drug. One major circulating metabolite (1) was found in pooled human plasma samples, accounting for approximately half of the observed drug-related material. Isolation of metabolite 1 from urine samples followed by MS and NMR studies led to a putative structural assignment of 1 where hydroxylation of GSK2798745 occurred on the central ring, producing a penta-substituted cyclohexane structure containing three stereocenters. Two unique chemical syntheses of the proposed structure were developed to confirm the identity of metabolite 1 and provide access to gram quantities for biological characterization.
ABSTRACT
GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.
Subject(s)
Pyrrolidines/chemistry , Sulfonamides/chemistry , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Animals , Drug Evaluation, Preclinical , Half-Life , Humans , Inhibitory Concentration 50 , Pyrrolidines/metabolism , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity Relationship , Sulfonamides/metabolism , TRPV Cation Channels/metabolismABSTRACT
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
Subject(s)
Pulmonary Edema/drug therapy , Pyrrolidines/pharmacology , Sulfonamides/pharmacology , Sulfones/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , Humans , Male , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfones/chemistry , Sulfones/pharmacokineticsABSTRACT
Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
Subject(s)
Chemistry, Pharmaceutical/methods , Piperazines/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Taurine/analogs & derivatives , Urotensins/antagonists & inhibitors , Acamprosate , Animals , Aorta/metabolism , Drug Design , Humans , Hypertension/drug therapy , Models, Chemical , Piperazines/chemistry , Rats , Structure-Activity Relationship , Taurine/drug effectsABSTRACT
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Subject(s)
Chemistry, Pharmaceutical/methods , Urotensins/antagonists & inhibitors , Administration, Oral , Animals , Brain/metabolism , Chromatography, High Pressure Liquid , Diamines/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Receptors, Opioid, kappa/chemistry , Stereoisomerism , Structure-Activity Relationship , Urotensins/chemistryABSTRACT
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
