ABSTRACT
Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.
Subject(s)
Amidines/chemical synthesis , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Oxazines/chemical synthesis , Administration, Oral , Amidines/chemistry , Amidines/pharmacology , Animals , Benzoxazines , Biological Availability , Combinatorial Chemistry Techniques , Dogs , Drug Design , Fibrinolysin/antagonists & inhibitors , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Injections, Intravenous , Models, Molecular , Oxazines/chemistry , Oxazines/pharmacology , Rabbits , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacologyABSTRACT
The development of benzothiazine-1,1-dioxide derivatives as a new structural class of potent endothelin receptor antagonists is described. Structure-activity relationships (SAR) revealed that PD164800 (1) is a potent antagonist of the ETA receptor subtype.
Subject(s)
Dioxoles/chemical synthesis , Endothelin Receptor Antagonists , Thiazines/chemical synthesis , Animals , CHO Cells , Cricetinae , Dioxoles/chemistry , Dioxoles/pharmacology , Humans , Magnetic Resonance Spectroscopy , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship , Thiazines/chemistry , Thiazines/pharmacologyABSTRACT
A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.
Subject(s)
Angiotensin Receptor Antagonists , Antihypertensive Agents/chemical synthesis , Hydantoins/chemical synthesis , Hydantoins/pharmacology , Administration, Oral , Angiotensin II/antagonists & inhibitors , Angiotensin II/metabolism , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacology , Aorta/drug effects , Blood Pressure/drug effects , Haplorhini , Hydantoins/chemistry , Hydantoins/metabolism , Hypertension/drug therapy , In Vitro Techniques , Male , Rabbits , Rats , Rats, Sprague-Dawley , Receptors, Angiotensin/metabolism , Structure-Activity Relationship , Vasoconstriction/drug effectsABSTRACT
A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.
