ABSTRACT
The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.
Subject(s)
Aminopyridines , Proto-Oncogene Proteins c-myc , Rats , Animals , Proto-Oncogene Proteins c-myc/metabolism , Gene Expression Regulation , Transcription Factors/metabolism , BenzimidazolesABSTRACT
Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold hopping approach, which relied on use of an internal H-bond to replace a saturated heterocyclic ring. Optimization of the lead through investigation of both aryl regions revealed approaches to increase potency through substituents believed to enhance separate intramolecular and intermolecular H-bond interactions. A proposed internal H-bond between the amine and neighboring benzenesulfonamide was stabilized by electronically modulating the benzenesulfonamide. In the aryl ether moiety, substituents para to the nitrile demonstrated an electronic effect on TRPV4 recognition. Finally, the acyclic amines inactivated CYP3A4 and this liability was addressed by modifications that sterically preclude formation of a putative metabolic intermediate complex to deliver advanced TRPV4 antagonists as leads for discovery of novel medicines.
Subject(s)
Diamines/chemistry , Sulfonamides/chemistry , TRPV Cation Channels/antagonists & inhibitors , Animals , Cytochrome P-450 CYP3A/metabolism , Diamines/chemical synthesis , Diamines/metabolism , Diamines/pharmacokinetics , Drug Design , Humans , Hydrogen Bonding/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Protein Binding , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , TRPV Cation Channels/chemistry , TRPV Cation Channels/metabolismABSTRACT
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
A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure-activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.
Subject(s)
Drug Design , Pyrrolidines/chemistry , Sulfonamides/chemistry , Sulfonamides/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Rats , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/pharmacokineticsABSTRACT
Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.
Subject(s)
Aniline Compounds/chemistry , Aniline Compounds/pharmacology , TRPC Cation Channels/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Diglycerides/metabolism , Drug Discovery , HEK293 Cells , Humans , TRPC Cation Channels/metabolism , TRPC6 Cation ChannelABSTRACT
The Mannich reaction is one of the most widely utilized chemical transformations for the construction of nitrogen-containing compounds. With the increasing occurrence of nitrogen in drugs and natural products, highly asymmetric variants of the Mannich reaction are desirable. In this communication, we report the application of our dinuclear zinc catalyst to a highly asymmetric Mannich-type reaction to generate syn 1,2-amino alcohols.
Subject(s)
Amino Alcohols/chemistry , Catalysis , Imines/chemistry , Ketones/chemistry , Stereoisomerism , Zinc/chemistryABSTRACT
[structure: see text] A highly convergent synthesis of the proposed structure of amphidinolide A is reported. Instructive applications of several organometallic processes are illustrated, including a highly selective ring-closing metathesis reaction.