Synthesis and structure-activity relationships of novel benzimidazole and imidazo[4,5-b]pyridine acid derivatives as thromboxane A2 receptor antagonists

Abstract

A series of 1-benzylbenzimidazole and 3-benzylimidazo[4,5-b]pyridine substituted in the 2-position by an alkanoic or mercaptoalkanoic acid chain was synthesized for evaluation as potential thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists. The affinity of each compound for washed human platelet TXA2/PGH2 receptors was determined by radioligand binding studies using [125I]PTA-OH. Structure-activity relationships led to the conclusions that 2-alkanoic acid derivatives were slightly more potent than 2-mercaptoalkanoic acids and that compounds possessing a 3,3-dimethylbutanoic acid in the 2-position were definitely the most potent with Ki values of 4-39 nM (11a, 11g-x, 37a, 37f-o, 23a-c). The replacement of this 3,3-dimethylbutanoic acid side chain by a shorter one led to a marked decrease of affinity (11b and 11c; Ki = 5600 and 1700 nM, respectively). Compounds of benzimidazole and imidazo[4,5-b]pyridine series displayed similar potencies (11q and 23c have Ki values of 6 and 7 nM, respectively). The interesting pharmacological profile of compound 23a (UP 116-77: 4-[3-[(4-chlorophenyl)methyl]-6-chloroimidazo[4,5-b]pyridin-2-yl]- 3,3-dimethylbutanoic acid) and its excellent tolerance led us to select this derivative for further development.

Molecular modeling of the second extracellular loop of G‐protein coupled receptors and its implication on structure‐based virtual screening

“…For the evaluation of the virtual screening performance against the four different models (F, TM, L1, and L2) of the three different GPCR targets (DRD2, AA3R, TA2R), a database was prepared consisting of 990 drug‐like compounds randomly selected from our in‐house collection of commercially available compounds and 10 known receptor‐specific antagonists shown in Tables III–V. The 10 known antagonists of each receptor were manually selected among existing chemotypes for each activity class6, 20, 59–65 for their specificity and high affinity, and chosen to span the broadest chemical diversity for the different receptors. To avoid biasing virtual screening results, caution was given to select 990 drug‐like decoys covering similar property ranges as the true actives (see property ranges in Supplementary Table II) but structurally different from any known active (the highest similarity coefficient, expressed by the Tanimoto coefficient on SciTegic ECFP_4 circular fingerprint,66 of any decoy to any true active is 0.42).…”

An alternative total synthesis of pentosidine

“…The chemical shift for the methylene group neighboring N in 21 is d 3.17, but d 4.22 in the case of 22. Transformation of the pyridine N-alkylated isomer 22 afforded intermediate 18 [17,23,34]. The consistency of NMR spectra for the two individual samples of 18, and the NMR spectrum of a mixture of the two samples (in 1:1 ratio), added conclusive evidence that imidazopyridine 18 obtained through this route is identical with the product obtained from the synthesis shown in Scheme 6.…”

A straightforward synthesis of pentosidine framework

“…Furthermore, in 10 , the HNCH 2 vicinal coupling could be observed clearly in DMSO‐ d 6 , whereas no such coupling was seen for 11 . The reaction of 11 with carbon disulfide and further methylation of sulfur could only provide 4‐alkylated imidazo[4,5‐ b ]pyridine structure 9 [16]. Compound 9 obtained through this route was found to be identical with the product obtained from the synthesis shown in Scheme .…”