Denis E. Ryono

Preparation of peptidic α-hydroxy phosphonates a new class of transition state analog renin inhibitors

Abstract A stereoselective synthesis of α-hydroxy phosphonates, a new class of transition state analog inhibitors is described. Methods of incorporating neutral and basic amino acid residues at the N-terminus of α-hydroxy-β-amino dimethyl phosphonate 8 are discussed. Incorporation of this novel functionality in a tripeptidic framework suitable for the aspartyl protease renin has led to the development of potent inhibitors of this enzyme.

Peptidic α-hydroxy phosphinyls C-terminal modification methodology

Abstract Compound 4 is a suitable intermediate for making C-terminal mortifications of the transition state mimicking “α-hydroxy-phosphinyl” moiety. Its preparmion and application are described.

BMS-180560, an insurmountable inhibitor of angiotensin II-stimulated responses: comparison with losartan and EXP3174

1 This study compares the activity of BMS‐180560 (2‐butyl‐4‐chloro‐1‐[[1‐[2‐(2H‐tetrazol‐5‐yl)phenyl]‐1H‐indol‐4‐yl]methyl]‐1H‐imidazole‐5‐carboxylic acid), an insurmountable angiotensin II (AII) receptor antagonist, with that of losartan and EXP3174 in functional and biochemical models of AII‐receptor activation. 2 BMS‐180560 selectively inhibited [125I]‐Sar1Ile8AII ([125I]SI‐AII) binding to rat aortic smooth muscle (RASM) cell and rat adrenal cortical AT1 receptors (Ki = 7.6 ± 1.2 and 18.4 ± 3.9 nm respectively) compared to adrenal cortical AT2 receptors (Ki = 37.6 ± 1.3 μm). The Ki values of BMS‐180560 and EXP3174, but not losartan, varied as a function of the BSA concentration used in the assays, indicating that the diacid drugs bound to albumin. 3 BMS‐180560 (3–300 nm) increased the KD of SI‐AII for RASM cell AT1 receptors. Only at high concentrations of BMS‐180560 (300 nm) were Bmax values decreased. 4 BMS‐180560 inhibited AII‐stimulated contraction of rabbit aorta with a calculated KB = 0.068 ± 0.048 nm and decreased maximal AII‐stimulated contraction at 1 nm BMS‐180560 by 75%. In the presence of 0.1% BSA, a higher KB value (5.2 ± 0.92 nm) was obtained. Losartan behaved as a competitive antagonist with a KB = 2.6 ± 0.13 nm. Contraction stimulated by endothelin‐1, noradrenaline, KC1, or the TXA2 receptor agonist U‐46619 were unaffected by BMS‐180560 (1 nm). 5 All stimulated the acidification rates of RASM cells as measured by a Cytosensor microphysiometer with an EC50 of 18 nm. Losartan (30 nm) shifted the AII concentration‐effect curves in a competitive manner whereas BMS‐180560 (0.01 and 0.1 nm) decreased the maximum responses by 60 and 75% respectively. Inhibition by losartan and BMS‐180560 could be reversed following washout although recovery took longer for BMS‐180560. 6 In [3H]‐myoinositol‐labelled RASM cells, losartan (30 and 200 nm), shifted the EC50 for AII‐stimulated [3H]‐inositol monophosphate formation to higher values, with no change in the maximal response. By contrast, EXP3174 (0.1 to 1 nm) decreased the maximal response in a concentration‐dependent manner (17–55%). BMS‐180560 (3 and 10 nm) increased the EC50 for AII and decreased the maximum response by 30 and 80% respectively. The inhibition by EXP3174 and BMS‐180560 could be reversed by inclusion of losartan (200 nm) indicating that the inhibition was not irreversible. 7 In conclusion, BMS‐180560 is a potent, specific, predominantly competitive, reversible AII receptor antagonist, which displays insurmountable receptor antagonism. At concentrations of BMS‐180560 which have no effect on receptor number, BMS‐180560 produced insurmountable antagonism of AII‐stimulated second messenger formation, extracellular acidification, and smooth muscle contraction.

Design, synthesis and structure-activity relationships of azole acids as novel, potent dual PPAR alpha/gamma agonists.

The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.

Dual metalloprotease inhibitors. II. Effect of substitution and stereochemistry on benzazepinone based mercaptoacetyls

Abstract A structure-activity study of dual-acting ACE/NEP inhibitor 1A was initiated in order to ascertain what parameters effect in vitro activity versus ACE and NEP. Unlike NEP, ACE was found to be remarkably tolerant to a wide variety of permutations with respect to both the lactam nucleus and the pharmacophore side chain.

Discovery of azetidinone acids as conformationally-constrained dual PPARα/γ agonists

A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

Dual metalloprotease inhibitors. IV. Utilization of thiazepines and thiazines as constrained peptidomimetic surrogates in mercaptoacyl dipeptides

Abstract A structure-activity study of the dual acting ACE/NEP inhibitors related to 1a and 1b was undertaken to determine the parameters critical for activity versus ACE and NEP in vitro.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

Orally active prodrugs of quinoline-4-carboxylic acid angiotensin II receptor antagonists

Abstract Prodrug derivatization of a potent quinoline-4-carboxylic acid angiotensin II receptor antagonist was Undertaken as an approach to achieve improved oral activity. A dioxolenone carboxylic ester and an alkylated tetrazole prodrug both showed greater oral antihypertensive acivity in the salt-deplete spontaneously hypertensive rat and increased oral bioavailability relative to the parent compound.

DUAL METALLOPROTEASE INHIBITORS. III: UTILIZATION OF BICYCLIC AND MONOCYCLIC DIAZEPINONE BASED MERCAPTOACETYLS

Abstract A series of bicyclic and monocyclic diazepinones were incorporated as conformationally restricted dipeptide surrogates in mercaptoacetyl dipeptide dual-acting ACE/NEP inhibitors. A comparison was made between these two classes of compounds as well as with the previously disclosed ACE/NEP inhibitor 1. Compound 2a was found to exhibit high potency versus both enzymes in vitro as well as in vivo.