192804-72-1

Upstream product

• 752165-24-5 2-butyn-1-ol 
• 63349-52-0 methyl 4-iodophenylacetate 
• 1798-06-7 (4-iodophenyl)acetic acid 
• 927-74-2 3-Butyn-1-ol 

Downstream Products

• 164931-20-8 methyl 4-(4-hydroxy-1-butyl)phenylacetate 
• 192804-78-7 4-(4-iodobutyl)phenylacetic acid 
• 192804-76-5 methyl 4-(4-iodobutyl)phenylacetate 
• 192804-80-1 4-<4-(1H-imidazol-1-yl)butyl>phenylacetic acid 
• 188128-95-2 4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenylacetic acid 
• 1026444-17-6 [(S)-5-((S)-3-tert-Butoxy-2-{2-[4-(4-imidazol-1-yl-butyl)-phenyl]-acetylamino}-propionylamino)-5-(2-cyclohexyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester 
• 1027946-85-5 [(S)-5-[(S)-3-tert-Butoxy-2-(2-{4-[4-(2-methyl-imidazol-1-yl)-butyl]-phenyl}-acetylamino)-propionylamino]-5-(2-cyclohexyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester 
• 164931-25-3 (S)-6-Amino-2-[(S)-3-hydroxy-2-(2-{4-[4-(2-methyl-imidazol-1-yl)-butyl]-phenyl}-acetylamino)-propionylamino]-hexanoic acid (2-cyclohexyl-ethyl)-amide 
• 192804-81-2 4-[4-(2-iodo-1H-imidazol-1-yl)butyl]phenylacetic acid 
• 192804-82-3 4-[4-(2-ethyl-1H-imidazol-1-yl)butyl]phenylacetic acid 
• 192804-83-4 4-[4-(2-isopropyl-1H-imidazol-1-yl)butyl]phenylacetic acid 
• 192804-84-5 4-[4-(2-methyl-1H-benzimidazol-1-yl)butyl]phenylacetic acid 
• 1026034-27-4 [(S)-5-[(S)-3-tert-Butoxy-2-(2-{4-[4-(2-iodo-imidazol-1-yl)-butyl]-phenyl}-acetylamino)-propionylamino]-5-(2-cyclohexyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester 
• 1026688-12-9 [(S)-5-[(S)-3-tert-Butoxy-2-(2-{4-[4-(2-ethyl-imidazol-1-yl)-butyl]-phenyl}-acetylamino)-propionylamino]-5-(2-cyclohexyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester 

Relevant academic research and scientific papers

Histone Deacetylase Inhibitors for Enhancing Activity of Antifungal Agents

The present invention relates to compositions and methods to selectively treat fungal infection. More particularly, the invention relates to compounds, compositions thereof, and methods for selectively enhancing fungal sensitivity to antifungal compounds. The compositions of the invention are comprised of a combination of a histone deacetylase inhibitor, or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, agricultural formulation, prodrug or complex thereof, and an antifungal agent, the histone deacetylase inhibitor being a compound of Formula (I):

Compounds having beta adrenergic receptor agonist and muscarinic receptor antagonist activity

This invention provides compounds of formula I: wherein R1, R2, R4, R5, R6, R7, R8a, R8b, W, a, b, c and m are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both β2 adrenergic receptor agonist and muscarinic receptor antagonist activity. Accordingly, such compounds are expected to be useful as therapeutic agents for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

COMPOUNDS HAVING β2 ADRENERGIC RECEPTOR AGONIST AND MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY

This invention provides compounds of formula I wherein R1, R2, R3, R4, R5, R6, R7, R8a, R8b, W, a and b are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both β2 adrenergic receptor agonist and muscarinic receptor antagonist activity. Accordingly, such compounds are expected to be useful as therapeutic agents for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity

The invention is directed to compounds of formula I: wherein R1, R2, R3, R4, R5, R6, R7a, R7b, W, G1, G2, a, b, c, d and m are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

Azabicycloalkane compounds

This invention provides compounds of formula I: wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both β2 adrenergic receptor agonist and muscarinic receptor antagonist activity. Such compounds are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Biphenyl derivatives

This invention provides biphenyl derivatives of formula I: wherein R1, R2, R3, R4, R5, R6, R7, W, a, b and c are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The biphenyl derivatives of this invention possess both β2 adrenergic receptor agonist and muscarinic receptor antagonist activity and therefore, such biphenyl derivatives are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

DIARYLMETHYL AND RELATED COMPOUNDS

This invention provides compounds of formula I: wherein R1, R2, R3, R4, R5, R6, R7, Ar1, Ar2, E, a, b, c, and z are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both β2 adrenergic receptor agonist and muscarinic receptor antagonist activity. Such compounds are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Benzisoxazole-derived antidiabetic compounds

The instant invention is concerned with acetylphenols which are useful as antiobesity and antidiabetic compounds. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering or modulating triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility or for treating atherosclerosis are also disclosed.

Seryl-lysyl-based peptide and peptidomimetic inhibitors of N-myristoyl transferase as anti-infective agents

Seryl-lysyl-based peptide and peptidomimetic compounds are described as inhibitors of the enzyme N-myristoyl transferase to provide selective control of the fungal organism Candida albicans. Peptidomimetic compounds of particular interest are those of the formula: STR1 wherein R1 is selected form aminoalkyl, p-aminoalkylphenylalkyl, imidazolylalkylphenylalkyl, 2-alkylimidazolylalkylphenylalkyl, benzimidazolylalkylphenylalkyl and 2-alkylbenzimidazolylalkylphenylalkyl; wherein R2 is selected from hydrido, alkyl, cycloalkyl, akenyl, alkynyl, haloalkyl, benzyl, alkylphenylalkyl, alkoxyphenylalkyl, halophenylalkyl, phenethyl, cycloalkylalkyl, halocycloalkylalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl and naphthylalkyl; wherein Y is selected from carboxylic acid, hydroxamic acid, phosphonic acid and tetrazolyl; or a pharmaceutically-acceptable salt, amide or ester thereof. Compounds of the formula are species-specific inhibitors of C. albicans with little effect on human NMT enzyme and thus would be useful in treating C. albicans fungal infections in humans.

Design and synthesis of novel imidazole-substituted dipeptide amides as potent and selective inhibitos of Candida albicans myristoylCoA:protein N- myristoyltransferase and identification of related tripeptide inhibitors with mechanism-based antifungal activity

A new class of antifungal agents has been discovered which exert their activity by blockade of myristoylCoA:protein N-myristoyltransferase (NMT; EC 2.1.3.97). Genetic experiments have established that NMT is needed to maintain the viability of Candida albicans and Cryptococcus neoformans, the two principal causes of systemic fungal infections in immunocompromised humans. Beginning with a weak octapeptide inhibitor ALYASKLS-NH2 (2, k(i) = 15.3 ± 6.4 μM), a series of imidazole-substituted Ser-Lys dipeptide amides have been designed and synthesized as potent and selective inhibitors of Candida albicans NMT. The strategy that led to these inhibitors evolved from the identification of those functional groups in the high-affinity octapeptide substrate GLYASKLS-NH3 1a necessary for tight binding truncation of the C-terminus, replacement of the four amino acids at the N-terminus by a spacer group, and substitution of the glycine amino group with an N-linked 2- methylimidazole moiety. Initial structure-activity studies led to the identification of 31 as a potent and selective peptidomimetic inhibitor with an IC50 of 56 nM and 250-fold selectivity versus human NMT. 2- Methylimidazole as the N-terminal amine replacement in combination with a 4- substituted phenacetyl moiety imparts remarkable potency and selectivity to this novel class of inhibitors. The (S:S) stereochemistry of serine and lysine residues is critical for the inhibitory activity, since the (R,R) enantiomer 40 is 102-fold less active than the (S,S) isomer 31. The inhibitory profile exhibited by this new class of NMT ligands is a function of the pK(o) of the imidazole substituent as illustrated by the benzimidazole analog 35 which is about 10-fold less potent than 31. The measured pK(o) (7.1 ± 0.5) of 2-methylimidazole in 31 is comparable with the estimated pK(o) (~8.0) of the glycyl residue in the high-affinity substrate 1a. Groups bulkier than methyl, such as ethyl, isopropyl, or iodo, at the imidazole 2- position have a detrimental effect on potency. Further refinement of 31 by grafting an α-methyl group at the benzytic position adjacent to the serine residue led to 61 with an IC50 of 40 nM. Subsequent chiral chromatography of 61 culminated in the discovery of the most potent Candida NMT inhibitor 61a reported to date with an IC50 of 20 nM and 400-fold selectivity versus the human enzyme. Both 31 and 61a are competitive inhibitors of Candida NMT with respect to the octapeptide substrate GNAASARE-NH2 with K(i)(app) = 30 and 27 nM, respectively. The potency and selectivity displayed by these inhibitors are dependent upon the size and orientation of the o-substituent. An α-methyl group with the R configuration corresponding to the (S)-methyl- 4-alanine in 2 confers maximum potency and selectivity. Structural modification of 31 and 61 by appending an (S)-carboyl group β to the cyclohexyl moiety provided the less potent tripeptice inhibitors 73a and 73b with an IC50 of 1.45 ± 0.08 and 0.38 ± 0.03 μM, respectively. However, these tripeptides (73a and 73b) exhibited a pronounced selectivity of 560- and 2200-fold versus the human NMT. More importantly 73a displayed fungistatic activity against C. albicans with an EC50 ± 17 μM in cell culture. Compound 73b also exhibited a similar antifungal activity. An Arf protein gel mobility shift assay for monitoring intracellular myristoylation revealed that a single dose of 200 μM of 73a or 73b produced 50 >1000 μM against C. albicans NMT did not exhibit antifungal activity and produced no detectable reduction in Arf N-myristoylation in cultures of C. albicans. These studies confirm that the observed antifungal activity of 73a adn 73b is due to the attenuation of NMT activity and that NMT represents an attractive target for the development of novel antifungal agents.