BIOMAT Database Logo BIOMAT Database Logo

Discovery of potent cyclic GMP phosphodiesterase inhibitors. 2-Pyridyl- and 2-imidazolylquinazolines possessing cyclic GMP phosphodiesterase and thromboxane synthesis inhibitory activities. 1995

S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Biofor Inc., Waverly, Pennsylvania 18471, USA.

Moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor 2-phenyl-4-anilino-quinazoline (1) was identified utilizing MultiCASE assisted drug design (MCADD) technology. Modification of compound 1 was conducted at the 2-, 4-, and 6-positions of the quinazoline ring for enhancement of cGMP-PDE inhibitory activity. The 6-substituted 2-(imidazol-1-yl)-quinazolines are 1000 times more potent in in vitro PDE V enzyme than the well-known inhibitor zaprinast. The 6-substituted derivatives of 2-(3-pyridyl)quinazoline 84 and 2-(imidazol-1-yl)quinazoline 86 exhibited more than 1000-fold selectivity for PDE V over the other four PDE isozymes. In addition, cGMP-PDE inhibitors 64, 65, and 73 were found to have an additional property of thromboxane synthesis inhibitory activity.

UI MeSH Term Description Entries
D008297 Male Males
D011799 Quinazolines A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline
D001792 Blood Platelets Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. Platelets,Thrombocytes,Blood Platelet,Platelet,Platelet, Blood,Platelets, Blood,Thrombocyte
D002417 Cattle Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor. Beef Cow,Bos grunniens,Bos indicus,Bos indicus Cattle,Bos taurus,Cow,Cow, Domestic,Dairy Cow,Holstein Cow,Indicine Cattle,Taurine Cattle,Taurus Cattle,Yak,Zebu,Beef Cows,Bos indicus Cattles,Cattle, Bos indicus,Cattle, Indicine,Cattle, Taurine,Cattle, Taurus,Cattles, Bos indicus,Cattles, Indicine,Cattles, Taurine,Cattles, Taurus,Cow, Beef,Cow, Dairy,Cow, Holstein,Cows,Dairy Cows,Domestic Cow,Domestic Cows,Indicine Cattles,Taurine Cattles,Taurus Cattles,Yaks,Zebus
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013928 Thromboxane A2 An unstable intermediate between the prostaglandin endoperoxides and thromboxane B2. The compound has a bicyclic oxaneoxetane structure. It is a potent inducer of platelet aggregation and causes vasoconstriction. It is the principal component of rabbit aorta contracting substance (RCS). Rabbit Aorta Contracting Substance,A2, Thromboxane

Related Publications

S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Cyclic GMP phosphodiesterase inhibitors. 2. Requirement of 6-substitution of quinazoline derivatives for potent and selective inhibitory activity.
June 1994, Journal of medicinal chemistry,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Synthesis and evaluation of potent and selective c-GMP phosphodiesterase inhibitors.
January 1999, Bioorganic & medicinal chemistry letters,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Cyclic AMP phosphodiesterase and cyclic GMP phosphodiesterase activities of rat mammary tissue.
May 1984, The Biochemical journal,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Cyclic GMP phosphodiesterase inhibitors. 1. The discovery of a novel potent inhibitor, 4-((3,4-(methylenedioxy)benzyl)amino)-6,7,8-trimethoxyquinazoline.
November 1993, Journal of medicinal chemistry,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Flavonoids are selective cyclic GMP phosphodiesterase inhibitors.
January 1979, Biochemical pharmacology,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Cyclic AMP and cyclic GMP phosphodiesterase activities in Hodgkin's disease lymphocytes.
January 1987, International journal of immunopharmacology,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Complex effects of inhibitors on cyclic GMP-stimulated cyclic nucleotide phosphodiesterase.
December 1983, The Journal of biological chemistry,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors.
September 2010, Bioorganic & medicinal chemistry letters,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Synthesis and cyclic GMP phosphodiesterase inhibitory activity of a series of 6-phenylpyrazolo[3,4-d]pyrimidones.
April 1996, Journal of medicinal chemistry,
S J Lee, and Y Konishi, and D T Yu, and T A Miskowski, and C M Riviello, and O T Macina, and M R Frierson, and K Kondo, and M Sugitani, and J C Sircar
Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1.
May 2018, Journal of medicinal chemistry,
Copied contents to your clipboard!