Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogs of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline

Abstract

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.

Functions of the N-terminal Region of Cyclic Nucleotide Phosphodiesterase 3 (PDE 3) Isoforms

“…first to indicate that lixazinone, a known PDE3 inhibitor (32,33), is a more potent inhibitor of the short forms of PDE3A than of PDE3B. This observation may be of potential functional and clinical significance since PDE3A isoforms with M r values similar to that predicted for recombinant H3A-⌬189, i.e.…”

In-vitro investigation of oxazol and urea analogues of morphinan at opioid receptors

“…Upon cyclization of 17 and 18 with 1, 1′-carbonyl-diimidazole, the amino-oxazoles 9 and 10 were obtained in moderate yields. 13 After triflation of the phenols (1 & 2), the corresponding triflates were subjected to palladiumcatalyzed amination yielding the amines 3 and 4 in moderate yields. 5-6 The mono substituted urea targets 11 and 12 were made in 59~63% yield by treating 3 and 4 with KNCO in acetic acid.…”

“…The receptor binding affinities of the urea derivatives (11)(12)(13)(14) were evaluated. From the data shown in Table 1, it is noteworthy that the mono substituted urea analogs 11 and 12 retained the same affinity at the μ receptor, and a 3~5 fold decrease at κ and a 6.5 fold increase at δ for 11 were observed when compared with 3-aminocyclorphan (3) and 3-aminobutorphan (4).…”

“…7-8 We also wish to examine the effect of substitution of the 3-OH group with a series of urea analogues (11)(12)(13)(14). The urea group was introduced since the substitution of oxygen for nitrogen increases the ability to interact at opioid receptors by the formation of hydrogen bonds.…”

Copper‐catalyzed N‐Arylation of Imidazoles with Aryl or Heteroaryl Halides Facilitated by Dimethylglyoxime in Water

“…In contrast, the nucleophilic aromatic substitution of imidazoles by the activated aryl halides 14,15 or in particular, the copper-catalyzed Ullmann coupling of aryl halides with imidazoles and benzimidazoles represents a straightforward, inexpensive approach, albeit with the shortage of high reaction temperature or stoichiometric amounts of copper reagents, and accordingly, many procedures have been reported for their syntheses. Among them, Buchwald and co-workers first discovered that 1,10-phenanthroline 16 and its derivative 17 and other bidentate N,N-ligand such as diamines 18,19 could promote the cross-coupling reaction effectively under mild conditions.…”