Inhibitors of blood platelet cAMP phosphodiesterase. 4. Structural variation of the side-chain terminus of water-soluble 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives

Abstract

1-(Cyclohexylmethyl)-4-[4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b] quinolin-7-yl)oxy]-1-oxobutyl]piperazine (2) was previously identified as a potent, water-soluble inhibitor of human blood platelet cAMP phosphodiesterase and of induced aggregation in vitro that demonstrated effective antithrombotic activity in animal models of thrombosis. Although 2 exhibited 25% oral bioavailability in rats, pharmacokinetic studies conducted in monkeys revealed that the parent compound was less than 5% bioavailable, the result of extensive first-pass biotransformation in the liver. In an effort to identify potent platelet aggregation inhibitors with enhanced metabolic stability, the side-chain amide moiety of 2 was replaced with chemically more stable urea (6a-s), sulfonamide (13a-m), sulfone (19a-r), and tetrazole (23a-s) moieties. Many representatives from each of these structural types effectively combined potent inhibition of ADP-induced human platelet aggregation in vitro with excellent aqueous solubility, and several are superior to 2. Within each series, the N-(cyclohexylmethyl)-, N-(2-ethylbutyl)-, N-benzyl-, and N-(4-fluorobenzyl)-substituted derivatives were evaluated for in vitro metabolic stability by incubating with the S-9 fraction of monkey liver for 2 h, and the extent of biotransformation was compared with that of the prototype 2. The sulfone 19e and the tetrazoles 23e, 23g, 23j, and 23q were significantly more stable than 2 under these conditions, and 19e and 23e were selected for evaluation in vivo. Tetrazole 23e exhibited 72% bioavailability following ip administration to rats compared with 35% bioavailability for 2 and 19e under the same conditions. However, the oral bioavailability of 19e and 23e in the rat was estimated to be only 3%, suggesting that 19e and 23e are less readily absorbed from the gastrointestinal tract than 2.

Thioesters for the in vitro evaluation of agents to image brain cholinesterases

“…This intermediate was then reduced with sodium borohydride (Scheme 1), in a reaction adapted from an earlier procedure 34 . Thioesters were subsequently generated by esterification of this thiol with an acid chloride (Scheme 1).…”

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

“…In particular, groups at Warner-Lambert/Parke Davis [108], Syntex [109], and Boehringer Mannheim [110] pursued cardiotonic agents. The connection between PDE3 inhibition and antithrombotic activity of anagrelide and cilostamide led those and other groups to pursue such compounds from the perspective of anti-platelet agents [104,111]. The result of this intensive era of research was that the structures prepared form a continuum of quinazolinones, quinolinones, imidazolinones as represented in Figs 1 and 2, but also that PDE3 inhibitor research has been conducted with respect to the optimisation and measurement of only the PDE3A isoform which is the exclusive PDE3 in platelets and predominates in cardiac tissue.…”

The Core and Most Useful Molecules in Organic Chemistry

“…The average island includes fewer than three molecules. g) Examples of highly connected island molecules, whose total syntheses have either been reported—1) phyllanthoside11, 12, 2) a phosphodiesterase inhibitor11, 12—or not described in the literature—3) nimbin13, 14, 4) a diterpenoid from the Caribbean gorgonian E. calyculata 16…”