Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Amides/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Capsaicin/toxicity , Cyclohexanols/pharmacokinetics , Cyclohexanols/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Isoxazoles/pharmacokinetics , Isoxazoles/therapeutic use , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , TRPV Cation Channels/metabolism
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Acetamides/chemical synthesis , Antidiuretic Hormone Receptor Antagonists , Hypothalamo-Hypophyseal System/drug effects , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , Acetamides/chemistry , Acetamides/pharmacology , Animals , Caco-2 Cells , Humans , Inhibitory Concentration 50 , Male , Molecular Structure , Quinazolinones/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Antidiuretic Hormone Receptor Antagonists , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Humans , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Rats , Structure-Activity Relationship
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Amides/chemistry , Antihypertensive Agents/chemistry , Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Cyclohexanols/chemical synthesis , Cyclohexanols/pharmacokinetics , Hyperthermia, Induced , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , TRPV Cation Channels/metabolism
