ABSTRACT
Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11ßHSD1.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Camphor/chemistry , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrazolones/chemical synthesis , Pyrazolones/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Enzyme Activation/drug effects , Female , Hydrocortisone/blood , Inhibitory Concentration 50 , Mice , Molecular Structure , RatsABSTRACT
The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor ß (THR-ß) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-ß selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-ß over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.
Subject(s)
Drug Discovery , Dyslipidemias/drug therapy , Pyridazines/chemical synthesis , Thyroid Hormone Receptors beta/agonists , Uracil/analogs & derivatives , Animals , Bone Density/drug effects , Clinical Trials as Topic , Humans , Male , Mice , Mice, Inbred C57BL , Pyridazines/metabolism , Pyridazines/pharmacology , Pyridazines/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Uracil/chemical synthesis , Uracil/metabolism , Uracil/pharmacology , Uracil/therapeutic useABSTRACT
A new series of 7,8-disubstituted pyrazolobenzodiazepines based on the lead compound 1 have been synthesized and evaluated for their effects on mitosis and angiogenesis. Described herein is the design, synthesis, SAR, and antitumor activity of these compounds leading to the identification of R1530, which was selected for clinical evaluation.
ABSTRACT
High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.
Subject(s)
Diamines/pharmacology , Enzyme Inhibitors/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Diamines/chemical synthesis , Diamines/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, Inbred C57BL , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure-activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzodiazepines/therapeutic use , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Models, Molecular , Neovascularization, Pathologic/drug therapy , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Structure-Activity RelationshipABSTRACT
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Subject(s)
Indans/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Crystallography, X-Ray , Humans , Indans/chemistry , Indans/pharmacokinetics , Kinetics , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and lithium alkoxide-induced fragmentation reactions to provide butenolides, gamma-hydroxycyclohexenones, and/or gamma-butyrolactones. In general, product distribution is governed by two factors: (1) the nature of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones. Lithium hydroxide-induced fragmentation provides butenolides and gamma-hydroxycyclohexenones. In contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted gamma-butyrolactones along with a small amount of butenolides in limited cases. Fragmentation products induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of butenolides.
