Nonprostanoid prostacyclin mimetics. 5. Structure-activity relationships associated with [3-[4-(4,5-diphenyl-2-oxazolyl)-5- oxazolyl]phenoxy]acetic acid.
cis-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethenyl]phenoxy]acetic acid (3) was previously identified as a nonprostanoid prostacyclin (PGI2) mimetic that potently inhibits ADP-induced aggregation of human platelets with an IC50 of 0.18 microM. As part of an effort to further explore structure-activity relationships for this class of platelet inhibitor and to provide additional insight into the nonprostanoid PGI2 mimetic pharmacophore, the effect of constraining the cis-olefin moiety of 3 into various ring systems was examined. Incorporation of the cis-olefin of 3 into either an oxazole (26) or an unsubstituted pyrazole (35) heterocycle provided compounds that are equipotent with progenitor 3. However, the oxazole 11f, which is isomeric with 26, inhibits ADP-induced human platelet aggregation in vitro with an IC50 of 0.027 microM, 6-fold more potent than 3, 26, or 35. These results suggest that the central oxazole ring of 11f is functioning as more than a simple scaffold that provides optimal stereodefinition for interaction with the PGI2 receptor. The nitrogen atom of the central heterocycle of 11f is postulated to engage in hydrogen-bond formation with a donor moiety in the PGI2 receptor protein, an interaction not available to 26 due to the markedly different topology. In support of this contention, the crystal structures of 11f and 26 contain strong intermolecular hydrogen bonds between the carboxylic acid hydrogen atom and the nitrogen atom of the central oxazole ring. Although 11f and 26 are exact isosteres and could, in principle, adopt the same molecular packing arrangement in the solid state, this is not the case, and the intermolecular hydrogen-bonding interactions in 11f and 26 are accommodated by entirely different molecular packing arrangements. Incorporation of the olefin moiety of 3 into a benzene ring provided a compound, 40, over 60-fold weaker with an IC50 of 11.1 microM. The affinities of 11f, 26, 31, 32, and 40 for the human platelet PGI2 receptor, determined by displacement of [3H]iloprost, correlated with inhibition of platelet function. The solid-state structures of 11f, 26, 31, 32, and 40 were determined and revealed that the more potent compounds 11f and 26 adopt a relatively planar overall topography. In contrast, the central phenyl ring and the phenoxy ring of the weakly active compound 40 are rotated by 53 degrees from planarity. The chemical shifts of the protons of the phenoxy rings of 3, 11f, 18, 26, 31, 32, and 40 suggest that in solution 3, 11f, 18, and 26 adopt a planar conformation while 40 does not.(ABSTRACT TRUNCATED AT 400 WORDS)
Meanwell
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Division of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660.
Romine
J L
JL
Rosenfeld
M J
MJ
Martin
S W
SW
Trehan
A K
AK
Wright
J J
JJ
Malley
M F
MF
Gougoutas
J Z
JZ
Brassard
C L
CL
Buchanan
J O
JO
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D001667:Binding, Competitive; D003460:Crystallization; D011464:Epoprostenol / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D016285:Iloprost / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
D000085:Acetates; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C084677:BMY 45778; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D016285:Iloprost