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.
Palmer
Andreas M
AM
NYCOMED GmbH, Department of Medicinal Chemistry, Byk-Gulden-Strasse 2, Konstanz, Germany. andreas.palmer@nycomed,.com
Grobbel
Burkhard
B
Jecke
Cornelia
C
Brehm
Christof
C
Zimmermann
Peter J
PJ
Buhr
Wilm
W
Feth
Martin P
MP
Simon
Wolfgang-Alexander
WA
Kromer
Wolfgang
W
D000818:Animals; D001667:Binding, Competitive; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D054328:Proton Pump Inhibitors; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
D007093:Imidazoles; D054328:Proton Pump Inhibitors; D011714:Pyrans; D011725:Pyridines; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium