Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline.
Hybridization of structural elements of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline ring system common to the cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitors lixazinone (RS-82856, 1) and anagrelide (3) with complementary features of other PDE inhibitor cardiotonic agents prompted the design and synthesis of the title compounds 7a-d, 11, 12, and 13a,b. The necessary features of these compounds were determined within the framework of the proposed active-site models for the high affinity form of cAMP PDE inhibited by cGMP (type IV). Evaluation of these targets, both in vitro as inhibitors of platelet or cardiac type IV PDE or in vivo as inotropic agents in the pentobarbital-anesthetized dog model of congestive heart failure, showed that these structure possessed negligibly enhanced activities over the parent heterocyclic system, and remained significantly inferior to 1 in all respects. This difference is ascribed to the absence of the N-cyclohexyl-N-methylbutyramidyl-4-oxy side chain of 1. The proposal that the acidic lactam-type functionality, common to the type IV PDE inhibitor inotropic agents such as 4-6 and 8-10, mimics the polarizable cyclic phosphate moiety of cAMP suggested that the side chain of 1 may function as an effective surrogate for selected characteristics of the adenine portion of cAMP. However, the results of this study show that incorporation of adenine-like hydrogen-bonding functionalities common to other type IV PDE inhibitors into the 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline system did not enhance activity to the levels observed for 1 and analogues. These observations, coupled with the kinetic pattern of inhibition of type IV PDE observed for 1 and analogues, suggest that access to a secondary, lipophilic-tolerant binding site, possibly coincident with the adenine binding domain, and adjacent to the catalytic ribose-phosphate binding site of platelet and cardiac type IV PDE, is responsible for the increased potency of these compounds.
Venuti
M C
MC
Institute of Bio-Organic Chemistry, Syntex Research, Palo Alto, California 94304.
Stephenson
R A
RA
Alvarez
R
R
Bruno
J J
JJ
Strosberg
A M
AM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D004341:Drug Evaluation; D006333:Heart Failure / Q000201:enzymology; D006801:Humans; D009206:Myocardium / Q000201:enzymology; D010974:Platelet Aggregation / Q000187:drug effects; D011799:Quinazolines; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D011799:Quinazolines; C049443:lixazinone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C021139:anagrelide