ABSTRACT
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A(2B) antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A(2A) and A(1) receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A(2A) and A(1) receptors.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Benzothiazoles/pharmacology , Drug Discovery , Benzothiazoles/chemistry , Structure-Activity RelationshipABSTRACT
Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 µM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).
Subject(s)
Amides/chemistry , Amides/pharmacology , Carboxylic Acids/chemistry , Diabetes Mellitus/drug therapy , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Discovery , Obesity/drug therapy , Oxazoles/chemistry , Oxazoles/pharmacology , Administration, Oral , Amides/administration & dosage , Amides/pharmacokinetics , Animals , Cell Line , Diabetes Mellitus/enzymology , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Male , Mice , Obesity/enzymology , Oxazoles/administration & dosage , Oxazoles/pharmacokinetics , RatsABSTRACT
7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Benzothiazoles/pharmacology , Receptor, Adenosine A2B/metabolism , Xanthine/chemistry , Adenosine A2 Receptor Antagonists/chemistry , Benzothiazoles/chemistry , Structure-Activity RelationshipABSTRACT
CGS 35601 is a potent triple inhibitor of endothelin-converting enzyme-1, neutral endopeptidase 24.11, and angiotensin-converting enzyme. It inhibited the activities of these three enzymes with IC50 values of 55, 2 and 22 nM, respectively. In conscious rats, CGS 35601 suppressed the big endothelin-1-induced pressor response by 82% and 72% at 30 and 120 minutes, respectively, following injection at a dose of 10 mg/kg, intravenously. At the same dose, CGS 35601 increased plasma atrial natriuretic peptide (ANP) immunoreactivity by 170% for up to 4 hours in conscious rats infused with ANP, and it inhibited the angiotensin I-induced pressor response by 74-94% within the first 2 hours after dosing. Similar in vivo activities were also observed with its orally active prodrug, CGS 37808. This compound blocked the big endothelin-1- induced pressor response by 71% and 67% at 30 and 120 minutes, respectively, after an oral dose of 10 mgEq/kg in conscious rats. It also increased plasma ANP immunoreactivity by 103% for up to 4 hours and inhibited the angiotensin I-induced pressor response by an average of 49% within the first 4 hours after the same dosing regimen. By suppressing the biosyntheses of endothelin-1 and angiotensin II, two potent vasoconstrictors, while simultaneously potentiating the circulating levels of ANP, a vasorelaxant and diuretic, CGS 35601 and CGS 37808 may represent novel agents for the treatment of cardiovascular and renal diseases.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Aspartic Acid Endopeptidases/antagonists & inhibitors , Dipeptides/pharmacology , Indoles/pharmacology , Metalloendopeptidases/antagonists & inhibitors , Neprilysin/antagonists & inhibitors , Peptidyl-Dipeptidase A/drug effects , Prodrugs/pharmacology , Protease Inhibitors/pharmacology , Administration, Oral , Angiotensin II/metabolism , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Animals , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Atrial Natriuretic Factor/metabolism , Blood Pressure/drug effects , CHO Cells , Cricetinae , Cricetulus , Dipeptides/administration & dosage , Endothelin-1/metabolism , Endothelin-Converting Enzymes , Humans , Indoles/administration & dosage , Injections, Intravenous , Male , Metalloendopeptidases/genetics , Metalloendopeptidases/metabolism , Neprilysin/metabolism , Peptidyl-Dipeptidase A/metabolism , Prodrugs/administration & dosage , Protease Inhibitors/administration & dosage , Rabbits , Rats , Rats, Sprague-Dawley , Time Factors , TransfectionABSTRACT
Directed screening of metalloprotease inhibitors identified CGS 30084 (1) as a potent inhibitor of endothelin-converting enzyme-1 (ECE-1) in vitro (IC(50)=77 nM). Herein we report the syntheses and biological activities of analogues containing modified biphenyl moieties, bearing heterocyclic proximal rings. Compound 20, the thioacetate ethyl ester prodrug derivative of compound 19a, was found to be an orally active and potent inhibitor of ECE-1 activity in rats.
