Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel.

Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of acid-related diseases that are widespread and constitute a significant economical burden. Enantiomerically pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK 405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was established. In addition, efficacy and duration of the antisecretory action was examined for the most promising target compounds by 24 h pH-metry in the fistula dog and a significantly different SAR was observed as compared to the Ghosh Schild rat. Several tetrahydrochromenoimidazoles were identified that possessed a comparable profile as the candidate 4.

Spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9-indenes) as inhibitors of gastric acid secretion.

Asymmetric and symmetric spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9-indenes) were prepared using a synthetic approach that comprised a cross-metathesis reaction and an acid-catalyzed cycloisomerisation as key steps. The target compounds constitute potent inhibitors of the gastric proton pump enzyme with inhibitory activity comparable to potassium-competitive acid blockers (P-CABs) belonging to the known 9-aryl-7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridine series. Spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9,2'-indenes) represent the first example for P-CABs, in which the distance between the heterocyclic scaffold and the aryl residue has been modified, and are promising candidates for further development as anti-ulcer drugs.

5-Substituted 1H-pyrrolo[3,2-b]pyridines as inhibitors of gastric acid secretion.

A series of novel 1H-pyrrolo[3,2-b]pyridines was prepared relying on a copper iodide catalyzed cyclization of 2-prop-1-ynylpyridin-3-amines. A structure-activity relationship was established focusing on the influence of the substitution pattern in position 1, 3, and 5 of the heterocycle on anti-secretory activity, lipophilicity, and pK(a) value. Some of the compounds proved to be potent inhibitors of the gastric acid pump.

Novel imidazo[1,2-a]pyrazine derivatives as potent reversible inhibitors of the gastric H+/K+-ATPase.

A series of novel 6-substituted imidazo[1,2-a]pyrazines were synthesized via palladium catalyzed amino- or alkoxycarbonylation as key step. The anti-secretory activity of these compounds has been assessed in a binding assay against H(+)/K(+)-ATPase from hog gastric mucosa. Some of the compounds proved to be potent inhibitors of the gastric acid pump.

Synthesis and evaluation of 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as potassium-competitive acid blockers.

7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological properties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral ketones. The influence of the character of the substituents R3, R6, and Ar on the biological activity and the physicochemical properties of the target compounds was examined. In contrast to the parent system (R6 = H), compounds in which R6 represents a carboxamide residue generally show improved in vivo activity and favorable pKa/log D values. Whereas variation of R3 is useful to obtain target compounds with modified basicity and lipophilicity, strong inhibition of the H+/K+-ATPase and potent in vivo activity is observed for R3 = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion inhibiting action, whereas the (9R)-enantiomers are virtually inactive.

Preparation of tetrahydroimidazo[2,1-a]isoquinolines and their use as inhibitors of gastric acid secretion.

A series of novel tetrahydroimidazo[2,1-a]isoquinolines was prepared based on a hetero Diels-Alder reaction between an enamine and 1,2,4-triazine as key step. A structure-activity relationship was established focussing on the influence of the substitution pattern in position 3 and 6 of the heterocycle on antisecretory activity, lipophilicity, and pK(a) value. Potent inhibitors of the gastric acid pump were identified.

Novel indanyl-substituted imidazo[1,2-a]pyridines as potent reversible inhibitors of the gastric H+/K+-ATPase.

A series of novel 8-indanylamino- and 8-indanyloxy-substituted imidazo[1,2-a]pyridines with reduced lipophilicity was synthesized from easily accessible starting compounds. The anti-secretory activity of these compounds has been assessed in a competitive binding assay against H(+)/K(+)-ATPase from hog gastric mucosa. Some of the compounds proved to be potent inhibitors of the gastric acid pump.

A concise synthesis of the octalactins.

The total synthesis of octalactins A and B has been achieved in 15 steps (longest linear sequence) and 10% overall yield from commercially available materials. Key steps include the Paterson-Aldol reaction for the rapid assembly of the carbonate 46, methylenation of 46 and subsequent Claisen rearrangement of the corresponding alkenyl-substituted cyclic ketene acetal to provide the core unsaturated medium-ring lactone 47, and the use of enzyme-mediated acetate deprotection in the presence of a medium-ring lactone.