BPS 334 Lecture 24: diuretics drug development
27 Nov 2016
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1981: captopril (ace inhibitor): first leads found by screening in 1965. 2007: aliskiren (renin inhibitor): first lead, pepstatin, 1971. First step, generation of a lead compound: (cid:1005)(cid:1013)(cid:1010)(cid:1004)"s: i(cid:374)terest i(cid:374) s(cid:272)ree(cid:374)i(cid:374)g s(cid:374)ake (cid:448)e(cid:374)o(cid:373) for (cid:448)asodilators a(cid:374)d a(cid:374)ti(cid:272)oagula(cid:374)ts, 1965: mix of peptides from south american pit viper increased action of bradykinin. Put information from 1 and 2 together to make assumptions about binding interactions of ace. Needed to recognize the different sites and mimic them with other compounds. Caused rashes because sulfhydryl forms disulfide bonds with cysteine residues on cellular proteins) Had enough positives to outweigh the negatives. No peptide bond, put nh back in but with an additional ch- (methylene group) Replaces sh with cooh but displaced it by attaching it to the methylene (no hydrolysable amide bond) Added a phenylalanine mimic to interact with s1 site. Lisinipril: also included a better mimic for histidine with a lysine side chain, nh fills up (cid:373)ore spa(cid:272)e, it"s a (cid:271)etter (cid:373)i(cid:373)i(cid:272) for histidine.
