Inhibitors of blood platelet cAMP phosphodiesterase. 3. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives with enhanced aqueous solubility

Abstract

Two series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives incorporating an additional site for acid salt formation were synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) and ADP-induced platelet aggregation. The objective of this study was to identify compounds that blended potent biological activity with a satisfactory level of aqueous solubility. From a series of 7-aminoimidazo[4,5-b]quinolin-2-ones, biological and physical properties were optimally combined in the 1-piperidinyl derivative 11c. However, this compound offered no significant advantage over earlier studied compounds as an antithrombotic agent in an animal model of small vessel thrombosis. A series of 7-alkoxy alkanoic piperazinamide derivatives, in which the additional basic nitrogen atom was remote from the heterocyclic nucleus and accommodated in a secondary binding region of the cAMP PDE enzyme, demonstrated greater intrinsic cAMP PDE inhibitory activity. Structural modifications of this series focused on variation of the piperazine substituent and side-chain length. The lipophilicity of the N-substituent influenced biological potency and aqueous solubility, with substituents of seven carbon atoms or less generally providing acceptable solubility properties. The N-(cyclohexylmethyl)piperazinamide 21h was identified from this series of compounds as a potent inhibitor of platelet cAMP PDE, IC50 = 0.4 nM, and ADP-induced platelet aggregation, IC50 = 0.51 microM after a 3-min exposure and 0.1 microM after a 15-min exposure of platelet-rich plasma to the drug. Evaluation of 21h and representative analogues in vivo using a rabbit model of small vessel thrombosis revealed significantly greater antithrombotic efficacy compared to that of previously studied compounds with similar intrinsic biological activity measured in vitro but inferior aqueous solubility.

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1

“…Piperazine has also found application in pharmaceutical design as a solubility-enhancing element, particularly in kinase inhibitors, with the BCR-ABL inhibitors imatinib ( 26 ) and bosutinib ( 27 ) and the cyclin-dependent kinase (CDK) 4/6 inhibitors palbociclib ( 28 ) and ribociclib ( 29 ) as representative examples . The piperazine moiety in the blood platelet aggregation inhibitors 30 and 31 conferred a significant enhancement of the aqueous solubility of these intrinsically insoluble phosphodiesterase 3 (PDE3) inhibitors which, in the absence of ionizable centers, exhibited poor pharmaceutical properties. , As a water-solubilizing appendage, a range of amines and diamines with differing architectures might be anticipated to be effective, as is observed with many other kinase inhibitors and analogues of 31 . , While this may generally be the case, there will be exceptions, as exemplified by 26 . The distal protonated nitrogen atom of the piperazine moiety of 26 engages the backbone carbonyls of Ile360 and His361 of the ABL kinase as H-bond acceptors in a bidentate interaction that contributes to potency, conferring sensitivity to the architecture of the diamine in this specific example .…”

“…50 The piperazine moiety in the blood platelet aggregation inhibitors 30 and 31 conferred a significant enhancement of the aqueous solubility of these intrinsically insoluble phosphodiesterase 3 (PDE3) inhibitors which, in the absence of ionizable centers, exhibited poor pharmaceutical properties. 51,52 As a water-solubilizing appendage, a range of amines and diamines with differing architectures might be anticipated to be effective, as is observed with many other kinase inhibitors and analogues of 31. 50,51 While this may generally be the case, there will be exceptions, as exemplified by 26.…”

“…51,52 As a water-solubilizing appendage, a range of amines and diamines with differing architectures might be anticipated to be effective, as is observed with many other kinase inhibitors and analogues of 31. 50,51 While this may generally be the case, there will be exceptions, as exemplified by 26. The distal protonated nitrogen atom of the piperazine moiety of 26 engages the backbone carbonyls of Ile360 and His361 of the ABL kinase as H-bond acceptors in a bidentate interaction that contributes to potency, conferring sensitivity to the architecture of the diamine in this specific example.…”

Solid-Phase Synthesis of Imidazo[4,5-b]pyridin-2-ones and Related Urea Derivatives by Cyclative Cleavage of a Carbamate Linkage

“…1,3-Dihydro-2 H -benzimidazol-2-ones ( 1 ) and related cyclic urea derivatives are useful heterocyclic building blocks and are prominent structural elements of compounds demonstrating a wide variety of pharmacological and biochemical properties. Examples of pharmacological activity exhibited by benzimidazol-2-ones 1 include antagonism of neurotransmitter receptors, inhibition of aldose reductase, antiulcer and antisecretory properties, and modulation of ion channels. − Furthermore, the closely related imidazo[4,5- b ]pyridin-2-ones ( 2 ) and imidazo[4,5- b ]quinolin-2-ones ( 3 ) have been described as potent inhibitors of blood platelet cAMP phosphodiesterase (PDE) (Figure ). −

1 Biologically active cyclic urea derivatives.

1 Solid-Phase Synthesis of 1,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-2-one 9 { 1 } a a Reagents and conditions: (a) phosgene (5 equiv, 1 M solution in toluene), THF, room temp, 8 h; (b) 4-nitrophenyl chloroformate (4 equiv), NMM, DCM, room temp, 16 h; (c) 2-amino-3-nitropyridine (4 equiv), BSA (5 equiv), DMAP (4 equiv), DMF, room temp, 16 h; (d) SnCl 2 ·2H 2 O (10 equiv, 1 M in DMF), 30 °C, 16 h; (e) MP-CO 3 (3 equiv), DMF (containing 1.5% AcOH), 60 °C, 16 h.

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“…[1][2][3][4] Furthermore, the closely related imidazo [4,5-b]pyridin-2-ones (2) and imidazo [4,5-b]quinolin-2-ones (3) have been described as potent inhibitors of blood platelet cAMP phosphodiesterase (PDE) (Figure 1). [5][6][7][8][9] A polymer-assisted solution-phase synthesis of a benzimidazol-2-one library has been reported by our research group. 10 To extend our structure-activity relationship study, we required a versatile synthetic route to rapidly generate and purify imidazo [4,5-b]pyridin-2-one derivatives.…”