Drug discovery anti-acid drugs

Finally, libraries aimed to chiral resolution of racemates will be covered here in particular, the use of chiral stationary phases (CSPs) has recently been reported for the identification of materials to be used for chiral separation of racemates by HPLC. The group of Frechet reported the selection of two macroporous poly methacrylate-supported 4-aryl-1,4-dihydropyrimidines (DHPs) as CSPs for the separation of amino acid, anti-inflammatory drugs, and DHP racemates from an 140-member discrete DHP library (214,215) as well as a deconvolutive approach for the identification of the best selector phase from a 36-member pool library of macroporous polymethacrylate-grafted amino acid anilides (216,217). Welch and co-workers (218,219) reported the selection of the best CSP for the separation of a racemic amino acid amide from a 50-member discrete dipeptide iV-3,5-dinitrobenzoyl amide hbrary and the follow-up, focused 71-member library (220). Wang and Li (221) reported the synthesis and the Circular Dichroism- (CD) based screening of a 16-member library of CSPs for the HPLC resolution of a leucine ester. Welch et al. recentiy reviewed the field of combinatorial libraries for the discovery of novel CSPs (222). Dyer et al. (223) reported an automated synthetic and screening procedure based on Differential Scanning Calorimetry (DSC) for the selection of chiral diastereomeric salts to resolve racemic mixtures by crystallization. Clark Still rejxrrted another example which is discussed in detail in Section 9.5.4. 

DRUG DISCOVERIES G. Anti-acid drugs B. Hopes and limits for drug... 

Indazoles have been used as the biosteres of indoles in drug discovery. In the synthesis of the nonsteroidal anti-inflammatory drug (NSAID) bendazac, benzylaniline was used as its starting material. Nitrosolation was accomplished using nitrous acid. The resulting A-nitroso intermediate was reduced with sodium thiosulfate to the corresponding hydrazine, which cyclized to the indazolone. Subsequent alkylation with methyl chloroacetate was followed by hydrolysis to deliver bendazac. 

During the last ten years numerous discoveries were made in this field, and research was initiated in a large number of new areas. Among the mile-stones of this last decade were the isolation of the potent endoperoxide intermediates the discovery of non-steroidal anti-inflammatory drugs as inhibitors of the fatty acid cyclooxygenase the discovery of the mutually antagonistic endoperoxide products. 

---