Atrial natriuretic peptide clearance inhibitors which resist degradation

A linear peptide compound having natriuretic, diuretic and/or vasodilator activity in mammals, which has the formula:

• Z.sub.1 Z.sub.2 -AA.sub.109 -AA.sub.110 -AA.sub.111 -AA.sub.112 -AA.sub.113 -Z.sub.3 ( 1)
• wherein AA.sub.109 -AA.sub.110 -AA.sub.111 -AA.sub.112 -AA.sub.113 is selected from the group consisting of
• ______________________________________ R(I/M)DRI RM DIR R(I/M)DRL K(I/M)DRI RLDRI R(I/M)DRM Q(I/M)DRI R(I/M)ERI R(I/M)DRM RVDRI R(I/M)DKI R(I/M)DRI and DI DRI R(I/M)DQI R(I/M)DRV ______________________________________
• wherein indicates the D form of the amino acid preceding it;
• and
• wherein Z.sub.1 is ##STR11## wherein Z.sub.2 is a spacer group capable of providing a spaced dimension of 4.5-15 angstroms between AA.sub.109 and the PhCH.sub.2 -- of Z.sub.1 selected from the group consisting of
• (a) --(AA).sub.a -- wherein AA is an amino acid and a is 1 or 2;
• (b) --(P).sub.n --(CO)--.sub.x wherein x is 0 or 1, n is 1-6, and P is CH.sub.2 wherein 1-2 of said --CH.sub.2 -- groups can be replaced by NH, provided N-N does not occur;
• and
• (c) --(O).sub.m --B--(O).sub.m --(CO).sub.x -- wherein x is 0 or 1, each m is 0-3, wherein the sum of m is 5 or less, --B-- is a saturated or unsaturated five- or six-membered ring optionally containing an N heteroatom, and O is CH.sub.2 or NH, provided --N--N-- does not occur;
• Z.sub.3 is (OH), NH.sub.2, or NHR" wherein R" is alkyl (1-10C);
• and
• wherein one or more of the amide linkages between adjacent amino acid residues may optionally be replaced by a linkage selected from the group consisting of --CH.sub.2 NH--, --CH.sub.2 S--, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --COCH.sub.2 --, --CH(OH)CH.sub.2 -- and --CH.sub.2 SO--.