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
The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23⯰C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.
Subject(s)
Antioxidants/pharmacology , Cyclobutanes/pharmacology , Drug Discovery , Isothiocyanates/pharmacology , NF-E2-Related Factor 2/metabolism , Signal Transduction/drug effects , Animals , Antioxidants/chemical synthesis , Antioxidants/pharmacokinetics , Cell Line , Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacokinetics , Gene Expression , Heme Oxygenase-1/genetics , Humans , Isothiocyanates/chemical synthesis , Isothiocyanates/pharmacokinetics , Kelch-Like ECH-Associated Protein 1/metabolism , Mice, Inbred C57BL , Molecular Structure , Oxidative Stress/drug effects , Rats , Solubility , Structure-Activity Relationship , Sulfoxides , Thiocarbamates/chemical synthesis , Thiocarbamates/pharmacokinetics , Thiocarbamates/pharmacologyABSTRACT
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
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Pyrazoles/pharmacology , Thiazoles/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Binding Sites/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The discovery of potent and selective cyanamide-based inhibitors of the cysteine protease cathepsin C is detailed. Optimization of the template with regard to plasma stability led to the identification of compound 17, a potent cathepsin C inhibitor with excellent selectivity over other cathepsins and potent in vivo activity in a cigarette smoke mouse model.
ABSTRACT
A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.
Subject(s)
Benzhydryl Compounds/chemical synthesis , Bronchodilator Agents/chemical synthesis , Quinuclidines/chemical synthesis , Receptor, Muscarinic M3/antagonists & inhibitors , Animals , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Biological Availability , Bronchi/drug effects , Bronchi/physiology , Bronchoconstriction/drug effects , Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Humans , In Vitro Techniques , Mice , Models, Molecular , Muscle Contraction , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Quinuclidines/chemistry , Quinuclidines/pharmacology , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
N,N'-diarylsquaramides were prepared and evaluated as antagonists of CXCR2. The compounds were found to be potent and selective antagonists of CXCR2. Significant differences in SAR was observed relative to the previously described N,N'-diarylurea series. As was the case in the N,N'-diarylurea series, placing sulfonamide substituent adjacent to the acidic phenol significantly reduced the clearance in rat pharmacokinetic studies.
Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Cyclobutanes/pharmacokinetics , Receptors, Interleukin-8B/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacology , Urea/pharmacokinetics , Animals , CHO Cells , Chemical Phenomena , Chemistry, Physical , Cricetinae , Cricetulus , Indicators and Reagents , Mass Spectrometry , Phenols/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of 3-substituted N,N'-diarylureas was prepared and the structure-activity relationship relative to CXCR2 receptor affinity as well as their pharmacokinetic properties were examined. In vitro microsomal metabolism studies indicated that the lower clearance rates of the 3-sulfonamido-substituted compounds were most likely due to the suppression of glucuronidation.
Subject(s)
Receptors, Interleukin-8B/antagonists & inhibitors , Sulfonylurea Compounds/chemistry , Administration, Oral , Animals , Biological Availability , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Protein Binding/drug effects , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , Receptors, Interleukin-8B/metabolism , Sulfonylurea Compounds/metabolism , Sulfonylurea Compounds/pharmacologyABSTRACT
N,N'-Diarylureas were prepared, and the structure-activity relationship relative to the CXCR2 receptor was examined. This led to the identification of a potent and highly selective CXCR2 antagonist, which in addition was shown to be functionally active both in vitro against human neutrophils and in vivo in rabbit models of ear edema and neutropenia.
