Daniel F. Veber

Approaches to peptidomimetics which serve as surrogates for the cis amide bond: novel disulfide-constrained bicyclic hexapeptide analogs of somatostatic.

Abstract In testing and refining our model of the receptor-bound conformation of the potent small-ring somatostatin analog cyclo-(Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11), we have investigated structures constrained within bicyclic systems. Specifically, we have incorporated the 8-membered -C ys-Cy s- unit in place of the -Phe11-Pro6-segment, thus achieving two aims: 1) constraint of the 11- > 6 amide bond to the cis geometry established for the cyclic hexapeptide; 2) positioning of the disulfide in place of the position-11 phenyl group, to act as surrogate for phenyl in receptor binding. Synthetic methodology which provides ready access to this class of compounds is presented, along with results of NMR spectral studies of the bicyclic systems. Biological assays show retention of high potency, in confirmation of our view of cyclo-cystine as a good mimetic for cis amide. Other reported mimetics for the cis amide bond are reviewed from the perspectives of comparative ease of accessibility and approximation of various amide bond parameters.

Potent dual antagonists of endothelin and angiotensin II receptors derived from α-phenoxyphenylacetic acids (Part III)

Abstract Screening a collection of α-phenoxyphenylacetic acid derived angiotensin II antagonists identified weak actives in an endothelin receptor binding assay. Synthetic modification of one of these leads has provided L-746,072 (13), a highly potent dual antagonist of angiotensin II and endothelin receptors.

Amide and α-keto carbonyl inhibitors of thrombin based on arginine and lysine: Synthesis, stability and biological characterization

We report structure-activity investigations in a series of tripeptide amide inhibitors of thrombin, and the development of a series of highly potent active site directed α-keto carbonyl inhibitors having the side chain of lysine at P1. Compounds of this class are unstable by virtue of reactivity at the electrophilic carbonyl and racemization at the adjacent carbon (CH). Modifications of prototype α-keto-ester 8a have afforded analogs retaining nanomolar Ki. Optimal potency and stability have been realized in α-keto-amides 11b (Ki = 2.8 nM) and 11c (Ki = 0.25 nM)

Selective non-peptide ligands for an accommodating peptide receptor. Imidazobenzodiazepines as potent cholecystokinin type b receptor antagonists

A series of imidazobenzodiazepines, non-peptide antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by chemical modification of the benzodiazepine ring system embedded within the CCK-B antagonist L-365,260, these compounds display CCK-B/CCK-A selectivity and some analogs have receptor binding affinities in the subnanomolar range. This group of novel imidazobenzodiazepines, among which N-[(2S,4R)-methyl-6-phenyl-2,4-dihydro-1H-imidazo[1,2- alpha][1,4]benzodiazepin-4-yl]-N-[3-methylphenyl]-urea (12) is the principal compound, expands the structural diversity of the collection of non-peptide CCK-B antagonists and will be useful in further delineating the function of CCK in the central nervous system.

Benzolactams as non-peptide cholecystokinin receptor ligands

A series of 1,3-substituted benzolactams are reported which are nonpeptidal receptor ligands of the peptide hormone cholecystokinin (CCK). These compounds are composites of potent, selective benzolactam CCK-A antagonists and unique structural elements which have been demonstrated to enhance the affinity of certain 1,4-benzodiazepine CCK-A antagonists for the CCK-B receptor.

Non-peptide oxytocin antagonists: identification and synthesis of a potent camphor aminosuccinimide

Abstract The structure activity relationships of a series of non-peptide oxytocin antagonists containing a camphor aminosuccinimide as a key structural element were investigated. A potent and selective analog was identified and prepared in diastereomerically pure form starting from aspartic acid.

Bradykinin agonist activity of a novel, potent oxytocin antagonist

From a series of potent cyclic hexapeptide oxytocin (OT) antagonists, a compound that exhibited significant bradykinin (BK) agonist activity was identified. L-366,811 (cyclo[L-proline-D-tryptophan-L-isoleucine-D-pipecolic acid-L-piperazine-2-carboxylic acid-N-Me-D-phenylalanine]) stimulated phosphatidylinositol (PI) turnover in rat uterine slices in vitro (approximately EC50, 2 microM) with a maximal effect (15-fold increase over basal) greater than that obtained for either BK or OT. L-366,811 also elicited dose-related contractions of the isolated rat uterus, producing measurable effects at 100 nM. Several other equally potent OT antagonists from the cyclic hexapeptide structural class were either less potent or inactive as activators of uterine PI turnover or contractility. The stimulatory effects of L-366,811 on uterine PI turnover and contractions were blocked by BK antagonists but not by an arginine vasopressin (AVP)/OT antagonist. In radioligand binding studies, L-366,811 exhibited moderate affinity (IC50, 360 nM) for the [3H]BK binding site in rat uterus, consistent with its potency in the functional models. These results indicate that L-366,811 exhibits BK agonist activity in rat uterus in vitro.

Side Chain Conformations of Somatostatin Analogs when Bound to Receptors

Conformationally based design has resulted in greatly simplified constrained analogs of somatostatin which show a high degree of metabolic stability and improved duration of action.