Reverse transcriptase inhibitors, nevirapine, efavirenz, and delavirdine

Reverse transcriptase inhibitors, nevirapine, efavirenz, and delavirdine 

A number patents and publications describe sedative or antidepressant properties for quinazolinethiones such as 3 related to the efavirenz lead Chemical instability of the lead structure 1, due to the masked ketone at the 4-position, was addressed by replacing the ethoxy group with a carbon linked substituent. A focus on replacing the thiourea functionality because of potential toxicity led to urea analogs, and subsequent efforts were directed toward solving the low metabolic stability of the V-methyl group. This was attained by a switch to the benzoxazinone system 

The lead 4 for delavirdine (6) was discovered in a screened set of 1,500 computationally diverse representatives of the Upjohn compound collection. There is only one literature ref. to the delavirdine lead structural type, exemplified by compound 7, prior to the disclosure of RT inhibitory activity for this class. Rapid SAR expansion of the lead was enabled by A/-benzyl connectivity and many alkylated and acylated variations of the upper portion of the piperazine scaffold were explored. Ultimately the acylindole, initially bearing a 5-methoxy substituent as in the first clinical candidate atevirdine (5), emerged as preferred. This was found to be metabolicaUy labile and was subsequently replaced with the methylsulfonamide group. Early work also identified the A/-ethyl substituent of the lead as a potential metabolic liability and, although this pattern was retained in the first clinical candidate, it was replaced by the V-isopro-pyl substituent in the approved drug, delavirdine (6). 

Structures related to the nevirapine lead 8 are well represented in the patent and scientific literature, since the core system is similar to that in the approved drug piren-zepine (10). Initial SAR efforts were driven largely by metabolic instability associated with each of the V-alkyl substituents. An acceptable profile was achieved with two changes. First, by modifying the attachment point of the methyl group from the 5- to the 4-position the extent of 

It is important to emphasize that, for these three examples, the lead structures, which act by a unique allosteric mode of inhibition, would not have been discovered by any other method available at the time, that is, were it not for the application of a screening approach to lead identification this class of drugs might not have emerged to find use in the clinic (Box 7.3). 

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