Synthesis and cyclic GMP phosphodiesterase inhibitory activity of a series of 6-phenylpyrazolo[3,4-d]pyrimidones.

A series of 6-phenylpyrazolo[3,4-d]pyrimidones is described which are specific inhibitors of cGMP specific (type V) phosphodiesterase. Enzymatic and cellular activity as well as in vivo oral antihypertensive activity are evaluated. A n-propoxy group at the 2-position of the phenyl ring is necessary for activity. A series of products substituted at the 5-position in addition to the 2-n-propoxy was prepared and evaluated. This position can accommodate many unrelated groups. Amino derivatives were very potent but lacked metabolic stability. Substitution by carbon-linked small heterocycles provided both high levels of activity and stability. Cellular activity very often correlated with in vivo activity. Among the compounds, 1,3-dimethyl-6(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydr opyrazolo[3,4-d]pyrimidin-4-one (38) and 1-ethyl-3-methyl-6-(2-propoxy-5-(4-methylthiazol-2-yl)phenyl -1,5-dihy dropyrazolo[3,4-d]pyrimidin-4-one (59) displayed outstanding in vivo activities at 5 mg/kg/os and good metabolic stabilities.

Synthesis and activity against multidrug resistance in Chinese hamster ovary cells of new acridone-4-carboxamides.

A number of tricyclic carboxamides have been synthesized and tested to evaluate their ability to reverse multidrug resistance in the CHRC/5 cell line. Among them the acridone derivatives were the most potent. A key feature is the presence of a dimethoxybenzyl or phenethylamine cationic site, separated from the tricyclic lipophilic part by a carbamoylphenyl chain. Optimization led to compounds 2 orders of magnitude more active than the prototype inhibitors verapamil and amiodarone. On the basis of in vitro and in vivo activities, 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7- dimethoxyisoquinol-2-yl)ethyl]phenyl]-4-acridinecarboxamide (84) has been selected for further development.

Benzophenone derivatives: a novel series of potent and selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase.

A series of benzophenone derivatives has been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (RT) and the growth of HIV-1 in MT-4 cells. Through the use of the structure-activity relationships within this series of compounds and computational chemistry techniques, a binding conformation is proposed. The SAR also indicated that the major interactions of 1h with the RT enzyme are through hydrogen bonding of the amide and benzophenone carbonyls and pi-orbital interactions with the benzophenone nucleus and an aromatic function separated from the benzophenone by a suitable spacer group. The crystal structure of compound 1h has been determined. A number of compounds with potent inhibitory activity against HIV-1 RT and HIV in cellular assays at levels comparable with AZT and our efforts to identify a metabolically stable analogue are described.