- Discovery of TD-0212, an Orally Active Dual Pharmacology AT1 Antagonist and Neprilysin Inhibitor (ARNI)
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Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT1/NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.
- McKinnell, R. Murray,Fatheree, Paul,Choi, Seok-Ki,Gendron, Roland,Jendza, Keith,Olson Blair, Brooke,Budman, Joe,Hill, Craig M.,Hegde, Laxminarayan G.,Yu, Cecile,McConn, Donavon,Hegde, Sharath S.,Marquess, Daniel G.,Klein, Uwe
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- Copper-catalyzed cross-coupling of aryl-, primary alkyl-, and secondary alkylboranes with heteroaryl bromides
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A method for the Cu-catalyzed cross-coupling of both aryl and alkylboranes with aryl bromides is described. The method employs an inexpensive Cu-catalyst and functions for a variety of heterocyclic as well as electron deficient aryl bromides. In addition, aryl iodides of varying substitution patterns and electronic properties work well.
- Bergmann, Allison M.,Oldham, Adam M.,You, Wei,Brown, M. Kevin
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supporting information
p. 5381 - 5384
(2018/06/01)
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- PPARG MODULATORS FOR TREATMENT OF OSTEOPOROSIS
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The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.
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Page/Page column 240
(2015/11/09)
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- N-ARYLYLMETHYLINDAZOLE MODULATORS OF PPARG
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The invention provides molecular entities that bind with high affinity to PPARG (PPARy), inhibit cdJk5-mediated phosphorylation of PP ARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes or obesity. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.
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Page/Page column 77; 78
(2013/06/06)
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- N-BIPHENYLMETHYLINDOLE MODULATORS OF PPARG
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The invention provides molecular entities that bind with high affinity to PPARG (PPAR3), inhibit kinase-mediated, e.g., cdk5-mediated, phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, or inflammation. In methods of treatment of these conditions using a compound of the invention, the compound can avoid producing side effects of significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, in the patient receiving the compound. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.
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Page/Page column 89
(2012/12/14)
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- The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: A concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives
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A convenient and facile synthesis, in silico docking studies and in vitro biological evaluation of N-substituted 5-butylimidazole derivatives as potent Angiotensin II (ANG II) receptor type 1 (AT1) blockers (ARBs) has been reported in the current study. Our efforts have been directed towards the development of an efficient synthetic route allowing the facile introduction of substituents on the imidazole ring. In particular, a series of imidazole based compounds bearing the biphenyl moiety at the N - 1 position, a halogen atom at the C-4 and polar substituents such as hydroxymethyl, aldo or carboxy group at the C-2 position were designed and synthesized. These compounds were evaluated for binding to human AT1 receptor and for ANG II antagonism in vitro on isolated rat uterus. Among them, 5-butyl-1-[[2′-(2H-tetrazol-5-yl)biphenyl-4-yl] methyl]imidazole-2-carboxylic acid (30) exhibited higher binding affinity compared to the other analogues tested (-log IC50 = 8.46). The latter analogue was also found to be the most active in the rat uterotonic test (pA2 = 7.83). Importantly, the binding affinity was higher to that of losartan (-log IC50 = 8.25) indicating the importance of carboxy group at the C-2 position. Experimental findings are in good agreement with docking studies, which were undertaken in order to investigate ligand/AT1 receptor interactions.
- Agelis, George,Resvani, Amalia,Matsoukas, John,Durdagi, Serdar,Spyridaki, Katerina,Liapakis, George,Tumova, Tereza,Slaninova, Jirina,Giannopoulos, Panagiotis,Mavromoustakos, Thomas,Vlahakos, Demetrios
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p. 358 - 374,17
(2020/07/30)
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- DUAL-ACTING ANTIHYPERTENSIVE AGENTS
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In one aspect, the invention relates to compounds having the formula: wherein: Ar, r, Z, X, R3, and R5-7 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.
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Page/Page column 49-50
(2010/02/17)
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- DUAL-ACTING ANTIHYPERTENSIVE AGENTS
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The invention relates to compounds having the formula: (I) wherein: Ar, r, R3, Z, X, and R5-7 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.
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Page/Page column 88-89
(2009/04/25)
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- Dual-acting antihypertensive agents
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The invention is directed to compounds having the formula: wherein: Ar, r, Y, Z, Q, W, X, and R5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.
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Page/Page column 42
(2008/12/04)
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- Dual-acting antihypertensive agents
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The invention is directed to compounds of formula I: wherein Ar, r, R3, X, and R5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula I have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and a process and intermediates for preparing such compounds.
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Page/Page column 39
(2008/12/07)
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- Dual-acting benzoimidazole antihypertensive agents
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The invention is directed to compounds having the formula: wherein: Ar, r, n, X, R2-3 and R5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.
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Page/Page column 44
(2009/01/24)
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- Process for producing tert-butyl 4′-methyl-2-biphenylcarboxlate
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A process for preparing tert-butyl 4′-methyl-2-biphenylcarboxylate characterized in that 4′-methyl-2-biphenylcarboxylic acid is reacted with isobutene in the presence of an acid catalyst. According to the present invention, tert-butyl 4′-methyl-2-biphenylcarboxylate having high quality can be conveniently and industrially advantageously prepared in a high yield under mild reaction conditions such as ambient temperatures without complicated procedures or any hazardous solvents.
- -
-
Example II-3
(2008/06/13)
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- N-substituted-1, 2, 4-triazolone compounds for treatment of cardiovascular disorders
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A class of N-substituted-1,2,4-triazolone compounds is described for use in treatment of cardiovascular disorders. Compounds of particular interest are angiotensin II antagonists of the formula wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl and hydroxyalkyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neo-pentyl, propylthio and butylthio; wherein each of R3 through R11 is hydrido with the proviso that at least one of R5 and R9 must be selected from COOH, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, wherein each of R42 and R43 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl. These compounds are particularly useful in treatment or control of hypertension and congestive heart failure.
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- Non-peptidic angiotensin-II-receptor-antagonists
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Novel compounds having the formula STR1 wherein R 1, R 2, X and Y are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
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Substituted Imidazo-fused 6-membered heterocycles of structural formula: STR1 wherein A, B, C, and D are independently carbon atoms or nitrogen atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.
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- A novel 3-substituted benzazepinone growth hormone secretagogue (L- 692,429)
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The 3-substituted benzazepinone, L-692,429 (compound 1), is the prototype compound of a novel class of compounds that stimulate release of growth hormone (GH). The molecule evolved from efforts to identify a non-peptide mimic of the growth hormone-releasing hexapeptide, GHRP-6. Compound 1 is prepared by sequential attachment of dimethyl-β-alanine and 2'- biphenylyltetrazole side chains to a chiral 3-aminobenzolactam nucleus. Comparison of the biological activity of 1 with the corresponding six- and eight-membered lactam analogs shows the seven-membered benzazepinone skeleton to be preferred. Molecular modeling of the structurally diverse GH secretagogues, L-692,429 and GHRP-6, was performed.
- Schoen,Pisano,Prendergast,Wyvratt Jr.,Fisher,Cheng,Chan,Butler,Smith,Ball
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p. 897 - 906
(2007/10/02)
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- IMIDAZOLE DERIVATIVES BEARING ACIDIC FUNCTIONAL GROUPS AT THE 5-POSITION, THEIR COMPOSITIONS AND METHODS OF USE AS ANGIOTENSIN II ANTAGONISTS
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There are disclosed substituted imidazole derivatives of Formula I bearing acidic functional groups which are useful as angiotensin II antagonists. STR1
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- Acyl amidine and acyl, guanidine substituted biphenyl derivatives
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Novel compounds are disclosed having the formula STR1 and wherein R1, R2 and R3 are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- SUBSTITUTED QUINAZOLINONES BEARING ACIDIC FUNCTIONALGROUPS AS ANGIOTENSIN II ANTAGONISTS
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Novel substituted quinazolinones of the formula (I) are useful as angiotensin II antagonists. STR1
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-
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- SUBSTITUTED PYRAZOLOPYRIMIDINES AS ANGIOTENSIN II ANTAGONISTS
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Novel substituted pyrazolopyrimidines of formula (I) which are useful as angiotensin II antagonists, are disclosed. STR1
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- Substituted quinazolinones as angiotensin II antagonists
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Novel substituted quinazolinones of the formula (I), which are useful as angiotensin II antagonists, are disclosed. STR1
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-
- Synthesis and Structure-Activity Relationships of Nonpeptide, Potent Triazolone-Based Angiotensin II Receptor Antagonists
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2,5-Dibutyl-2,4-dihydro-4--4'-yl>methyl>-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action.To explore the lipophilic pocket in the AII receptor interacting with the substituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinity and antagonism of AII-contracted rabbitaortic rings.It has been found that the pocket is very spacious and can accommodate different sizes of lipophilic groups and various functionalities.Acidic groups generally result in a slight decrease in binding affinity.Branched chains are unfavorable.The freedom of rotation around C2-C3 in the flexible side chain is crucial for good binding.The 2-phenylethyl-substituted triazolone analogue exhibits the highest in vitro potency among all compounds that have been synthesized.
- Huang, Horng-Chih,Reitz, David B.,Chamberlain, Timothy S.,Olins, Gillian M.,Corpus. Valerie M.,et al.
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p. 2172 - 2181
(2007/10/02)
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- SUBSTITUTED IMIDAZO-FUSED 6-MEMBERED HETEROCYCLCES AS ANGIOTENSIN II ANTAGONISTS
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Substituted Imidazo-fused 6-membered heterocycles of structural formula: STR1 wherein A, B, C, and D are independently carbon atoms or nitrogren atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.
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- ANGIOTENSIN II RECEPTOR BLOCKING IMIDAZOLES
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Substituted imidazoles such as STR1 are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.
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- Treatment of congestive heart failure with angiotensin 11 receptor blocking imidazoles
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Substituted imidazoles such as STR1 are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.
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- Nonpeptide Angiotensin II Receptor Antagonists: The Discovery of a Series of N-(Biphenylylmethyl)imidazoles as Potent, Orally Active Antihypertensives
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A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared.These N-(biphenylylmethyl)imidazoles, e.g. 2-butyl-1--4-chloro-5-(hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously.It has been found that the acidic group at the 2'-position of the biphenyl is essential.Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency.The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective.The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.
- Carini, David J.,Duncia, John V.,Aldrich, Paul E.,Chiu, Andrew T.,Johnson, Alexander L.,et al.
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p. 2525 - 2547
(2007/10/02)
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