Nathan B. Mantlo

Potent, orally absorbed glucagon receptor antagonists.

The SAR of 2-pyridyl-3,5-diaryl pyrroles, ligands of the human glucagon receptor and inhibitors of p38 kinase, were investigated. This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrr ole 49 (L-168,049), a potent (Kb = 25 nM), selective antagonist of glucagon.

Pyrroles and other heterocycles as inhibitors of P38 kinase

Investigation of furans, pyrroles and pyrazolones identified 3-pyridyl-2,5-diaryl-pyrroles as potent, orally bioavailable inhibitors of p38 kinase. 3-(4-pyridyl-2-(4-fluoro-phenyl)-5-(4-methylsulfinylphenyl)-pyrrol e (L-167307) reduces secondary paw swelling in the rat adjuvant arthritis model: ID50 = 7.4 mg/kg/b.i.d.

Substituted imidazoles as glucagon receptor antagonists.

A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds.

Imidazo[4,5-b]pyridine-based AT1 / AT2 angiotensin II receptor antagonists

Abstract The structure-activity relationships of 6-amido-imidazol [4,5-b]pyridine-based angiostensin II antagonists ( V demonstrate that high affinity for the AT1 and AT2 receptors is largely dependent upon the R1 and R4 substituents. Of this series, L-162,441 and L-162,620 exhibits subnanomolar (IC50) binding affinities to both AT1 and AT2 receptors and potent antihypertensive effects in animals upon oral administration.

A nonpeptidic agonist ligand of the human C5a receptor: Synthesis, binding affinity optimization and functional characterization

The structural optimization for binding affinity and attempted modification of agonist function of a nonpeptide ligand of the human C5a receptor is described.

In vitro pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl) [1,1]-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) inhibited specific 125I-[Sar1, Ile8]angiotensin II binding to angiotensin AT1 receptor (Ki = 0.11-0.20 nM) in rabbit aorta, rat adrenal and human angiotensin AT1 receptor in CHO (Chinese hamster ovary transformed) cells and to AT2 receptor (Ki = 0.14-0.23 nM) in rat adrenal and brain receptors. L-163,017 also had a high affinity in the presence of bovine serum albumin (2 mg/ml), for angiotensin AT1 and AT2 receptors on human adrenal (Ki 3.9 and 4.3 nM), aorta (Ki 0.45 and 0.96 nM) and kidney (Ki 3.6 and 2.3 nM). The much higher Ki values in human tissues were likely due to the presence of bovine serum albumin in the binding assay buffer since L-163,017 had Ki values of 0.13 +/- 0.04 and 2.0 +/- 0.04 nM in the absence and presence of bovine serum albumin, respectively, in inhibiting 125I-[Sar1,Ile8]angiotensin II binding to angiotensin AT1 receptor in rat adrenal membranes. Scatchard analysis of 125I-[Sar1,Ile8]angiotensin II binding in the presence of bovine serum albumin (2 mg/ml) in rabbit aorta and bovine cerebellum indicated a competitive interaction of L-163,017 with angiotensin AT1 and AT2 receptors (Ki values 2.5 and 2.1 nM respectively). L-163,017 inhibited angiotensin II-induced aldosterone release in rat adrenal demonstrating that L-163,017 acted as a competitive antagonist (pA2 = 9.9) and lacked agonist activity. L-163,017 also inhibited angiotensin II responses in rat vascular tissues. The specificity of L-163,017 was shown by its lack of activity on the above functional responses produced by other agonists and in several binding assays.

Evaluation of heterocyclic acid equivalents as tetrazole replacements in imidazopyridine-based nonpeptide angiotensin II receptor antagonists

Abstract A series of imidazol[4,5-b] pyridine AII antagonists incorporating heterocyclic acid equivalents, e.g., oxathiadiazoles, thiatriazoles, and dioxobenzothiadiazines, are exemplified as novel non-peptide AII receptor antagonists. The most potent antagonist in this series, L-161,177 (IC50 = 0.7 nM, rabbit aorta), bearing the oxathiadiazole, exhibited in vivo profile after both iv and oral administration to conscious rats.

In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for angiotensin AT2 receptors

Abstract L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[(2′-(N-(3-methyl-1-butoxy)carbonylaminosulfonyl)[1,1′]-biphenyl-4-yl]-methyl]-3H-imidazo-[4,5-b] is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.

ACIDIC PHENOLS: A NEW CLASS OF POTENT NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS

Abstract A series of imidazo[4,5-b]pyridine-based acidic phenols (Table 1,2) and biphenyl ethers (Table 3) are exemplified as novel non-peptide AII receptor antagonists. 0,0′-substituents which affect the acidity of the phenolic portion dramatically impact the activity of the compounds. The most potent antagonist in this series (Compound 13 , IC50 = 5 nM, rabbit aorta) exhibited good in vivo potency after both iv and oral administration to conscious rats.