ABSTRACT
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.
ABSTRACT
High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound 1, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker 19, which has good target activity and pharmacokinetic properties. Inhibitor 19 was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema.
ABSTRACT
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
Subject(s)
Pyrrolidines/chemistry , Receptors, Progesterone/agonists , Animals , Binding Sites , Carbamates/chemistry , Crystallography, X-Ray , ERG1 Potassium Channel , Endometriosis/drug therapy , Ether-A-Go-Go Potassium Channels/metabolism , Female , Humans , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Receptors, Progesterone/metabolism , Sulfonamides/chemistryABSTRACT
Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.
Subject(s)
Pyrrolidines/chemistry , Receptors, Progesterone/agonists , Administration, Oral , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Design , Models, Animal , Protein Structure, Tertiary , Pyrrolidines/administration & dosage , Pyrrolidines/chemical synthesis , Rats , Receptors, Progesterone/metabolismABSTRACT
We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition.
Subject(s)
Pyrrolidinones/chemistry , Receptors, Progesterone/agonists , Administration, Oral , Animals , Binding Sites , Drug Discovery , Ether-A-Go-Go Potassium Channels/metabolism , Haplorhini , Humans , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacokinetics , Rats , Receptors, Progesterone/metabolism , Structure-Activity RelationshipABSTRACT
Two classes of amino acid-derived heterocyclic progesterone receptor ligands were developed to address the metabolic issues posed by the dimethyl amide functionality of the lead compound (1). The tetrazole-derived ligands behaved as potent partial agonists, while the 1,2,4-triazole ligands behaved as potent full agonists.
Subject(s)
Receptors, Progesterone/agonists , Tetrazoles/chemical synthesis , Amino Acids/chemistry , Animals , Rats , Receptors, Progesterone/metabolism , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacokineticsABSTRACT
A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXRalpha will be disclosed.
Subject(s)
DNA-Binding Proteins/agonists , Indoles/chemical synthesis , Indoles/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Administration, Oral , Animals , Cholesterol/analysis , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Indoles/chemistry , Liver X Receptors , Macrophages/drug effects , Mice , Molecular Conformation , Molecular Structure , Orphan Nuclear Receptors , Rats , Structure-Activity RelationshipABSTRACT
The reaction of a 1,6-enyne with a hydrosilane catalyzed by Rh(acac)(CO)(2), Rh(4)(CO)(12), or Rh(2)Co(2)(CO)(12) under ambient CO atmosphere or N(2) gives 2-methyl-1-silylmethylidene-2-cyclopentane or its heteroatom congener in excellent yield through silylcarbocycization (SiCaC) process. The same reaction, but in the presence of a phosphite such as P(OEt)(3) and P(OPh)(3) under 20 atm of CO, affords the corresponding 2-formylmethyl-1-silylmethylidene-2-cyclopentane or its heteroatom congener with excellent selectivity through carbonylative silylcarbocycization (CO-SiCaC) process. The SiCaC reaction has also been applied to a 1,6-enyne bearing a cyclohexenyl group as the alkene moiety and a 1,7-enyne system. The functionalized five- and six-membered ring systems obtained by these novel cyclization reactions serve as useful and versatile intermediates for the syntheses of natural and unnatural heterocyclic and carbocyclic compounds. Possible mechanisms for the SiCaC and CO-SiCaC reactions as well as unique features of these processes are discussed.