ABSTRACT
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Subject(s)
Enzyme Inhibitors/pharmacology , Imines/pharmacology , Pyrimidinones/pharmacology , Renin/antagonists & inhibitors , Administration, Oral , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Imines/chemical synthesis , Imines/chemistry , Models, Molecular , Molecular Structure , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Renin/metabolism , Structure-Activity RelationshipABSTRACT
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Subject(s)
Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Quinoxalines/pharmacology , Sodium Channel Blockers/pharmacology , Spiro Compounds/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrroles/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Biological Availability , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Design , Humans , Mice , Mice, Nude , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Rats , Receptor, Transforming Growth Factor-beta Type I , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.
Subject(s)
Benzimidazoles/chemical synthesis , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cells, Cultured , Humans , Mice , Mice, Nude , Mink , Protein Structure, Tertiary , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Receptor, Transforming Growth Factor-beta Type I , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
An efficient protecting group controlled regioselective chromium(0)-mediated three-component higher order cycloaddition of tethered diynes with cyclic trienes that generates five rings and six stereogenic centers in one step is described. Following a sequence of reactions featuring a chemoselective Baeyer-Villiger rearrangement and a regioselective cyclopropane hydrogenolysis, the total synthesis of 9-epi-pentalenic acid was achieved.
