Short-acting 5-(trifluoromethyl)pyrido[4,3- d]pyrimidin-4(3 H)-one derivatives as orally-active calcium-sensing receptor antagonists

Structure–activity relationship studies, focused on the optimization of pharmacology and pharmacokinetics, are described for a series of short-acting 5-(trifluoromethyl)pyrido[4,3- d]pyrimidin-4(3 H)-one derivatives and calcium-sensing receptor antagonists. Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3- d]pyrimidin-4(3 H)-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.