ABSTRACT
The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.
ABSTRACT
Formal aromatic C-H insertion of rhodium(II) carbenoid was intensively investigated to develop a new methodology and probe its mechanism. Contrasting with the previously proposed direct C-H insertion, the mechanism was revealed to be electrophilic aromatic substitution, which was supported by substituent effects on the aromatic ring and a secondary deuterium kinetic isotope effect. Various isoquinolinones were synthesized intramolecularly via six-membered ring formation with high regio- and diastereoselectivity, while averting the common Buchner-type reaction. Intermolecularly, dirhodium catalyzed formal aromatic C-H insertion on electron-rich aromatics was also achieved.
Subject(s)
Carbon/chemistry , Hydrogen/chemistry , Isoquinolines/chemistry , Isoquinolines/chemical synthesis , Catalysis , Diazonium Compounds/chemistry , Kinetics , Models, Molecular , Molecular Conformation , Rhodium/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
Synthesis and structure-activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.
Subject(s)
Anabolic Agents/chemistry , Pyrimidinones/chemistry , Receptors, Calcium-Sensing/antagonists & inhibitors , Administration, Oral , Anabolic Agents/administration & dosage , Anabolic Agents/pharmacokinetics , Animals , Male , Parathyroid Hormone/metabolism , Pyrimidinones/administration & dosage , Pyrimidinones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Calcium-Sensing/metabolism , Structure-Activity RelationshipABSTRACT
By intramolecular C-H insertion of alpha-diazo-alpha-(phenylsulfonyl)acetamides, gamma-lactams such as the antidepressant agent rolipram were efficiently synthesized in a highly regioselective manner. N-Benzyl moieties were elaborated as amide protecting groups to enhance regioselectivity in C-H activation as well as chemoselectivity over addition reactions. [reaction: see text]