Selective HDAC inhibitors, and pharmaceutical compositions that include the same, are described herein for the treatment of cancer, immunological diseases, inflammatory diseases, and neurological diseases.

Selective HDAC inhibitors, and pharmaceutical compositions that include the same, are described herein for the treatment of cancer, immunological diseases, inflammatory diseases, and neurological diseases.

Identification and evaluation of a set of first-in-class potent inhibitors targeting a new cancer target, Grb2-associated binder˜1 (GAB1), which integrates signals from different signaling pathways and is frequently over-expressed in cancer ceils. Intensive computational modeling is utilized to understand the structure of the GAB1 pleckstrin homology (PH) domain and screened five million compounds. Upon biological evaluation, several inhibitors were found that induced large conformational changes of the target structure exhibited strong selective binding to GAB1 PH domain. Particularly, these inhibitors demonstrated potent and tumor-specific cytotoxicity in breast cancer cells. This targeting GAB1 signaling may be used for cancer therapy, especially for triple negative breast cancer patients.

Identification and evaluation of a set of first-in-class potent inhibitors targeting a new cancer target, Grb2-associated binder˜1 (GAB1), which integrates signals from different signaling pathways and is frequently over-expressed in cancer ceils. Intensive computational modeling is utilized to understand the structure of the GAB1 pleckstrin homology (PH) domain and screened five million compounds. Upon biological evaluation, several inhibitors were found that induced large conformational changes of the target structure exhibited strong selective binding to GAB1 PH domain. Particularly, these inhibitors demonstrated potent and tumor-specific cytotoxicity in breast cancer cells. This targeting GAB1 signaling may be used for cancer therapy, especially for triple negative breast cancer patients.

The invention described herein generally relates to novel therapeutic compounds, and in particular to carbonic anhydrase inhibitors as a narrow spectrum antibiotics against drug resistant bacteria and methods for treating those infection diseases in mammals using the described carbonic anhydrase inhibitors or a pharmaceutical formulation thereof.

The invention described herein generally relates to novel therapeutic compounds, and in particular to carbonic anhydrase inhibitors as a narrow spectrum antibiotics against drug resistant bacteria and methods for treating those infection diseases in mammals using the described carbonic anhydrase inhibitors or a pharmaceutical formulation thereof.

The disclosure relates to compounds of formula (I) useful in the treatment of tauopathies and Alzheimer's disease

##STR00001##

wherein A, R, W, Q, n, and m are described herein.

The disclosure relates to compounds of formula (I) useful in the treatment of tauopathies and Alzheimer's disease

##STR00001##

wherein A, R, W, Q, n, and m are described herein.

A compound, or a pharmaceutically acceptable salt thereof, having a structure of:

##STR00001##

wherein A is a ring; Y.sup.1 and Y.sup.2 are each independently N or C with the proper valency; X.sup.1 and X.sup.2 are each independently —NH—, —O—, —CH.sub.2—O—, —NH—CH.sub.2—, or —N(CH.sub.3)—CH.sub.2—, provided that when at least one of X.sup.1 and X.sup.2 is —CH.sub.2—O—, —NH—CH.sub.2—, or —N(CH.sub.3)—CH.sub.2— then the —CH.sub.2— is directly connected to A; a and b are each independently 0 or 1; c and d are each independently 0 or 1; Z.sup.1 and Z.sup.2 are each independently a heterocyclic; and R.sup.1 and R.sup.2 are each independently optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, amino, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; provided that if Y.sup.1 and Y.sup.2 are each C, then a is 1 and b is 1; provided that if Y.sup.1 and Y.sup.2 are each N, then a is 0 and b is 0; provided that if Y.sup.1 is N and Y.sup.2 is C, then a=0 and b=1; provided that if Y.sup.1 is C and Y.sup.2 is N, then a=1 and b=0; provided that if c=0 and d=0, then R.sup.1 and R.sup.2 are both amino; provided that if c is 1 and d is 1, then both R.sup.1 and R.sup.2 are not amino; provided that if c is 0 and d is 1, then R.sup.1 is amino and R.sup.2 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; and provided that if c is 1 and d is 0, then R.sup.2 is amino and R.sup.1 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

A compound, or a pharmaceutically acceptable salt thereof, having a structure of:

##STR00001##

wherein A is a ring; Y.sup.1 and Y.sup.2 are each independently N or C with the proper valency; X.sup.1 and X.sup.2 are each independently —NH—, —O—, —CH.sub.2—O—, —NH—CH.sub.2—, or —N(CH.sub.3)—CH.sub.2—, provided that when at least one of X.sup.1 and X.sup.2 is —CH.sub.2—O—, —NH—CH.sub.2—, or —N(CH.sub.3)—CH.sub.2— then the —CH.sub.2— is directly connected to A; a and b are each independently 0 or 1; c and d are each independently 0 or 1; Z.sup.1 and Z.sup.2 are each independently a heterocyclic; and R.sup.1 and R.sup.2 are each independently optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, amino, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; provided that if Y.sup.1 and Y.sup.2 are each C, then a is 1 and b is 1; provided that if Y.sup.1 and Y.sup.2 are each N, then a is 0 and b is 0; provided that if Y.sup.1 is N and Y.sup.2 is C, then a=0 and b=1; provided that if Y.sup.1 is C and Y.sup.2 is N, then a=1 and b=0; provided that if c=0 and d=0, then R.sup.1 and R.sup.2 are both amino; provided that if c is 1 and d is 1, then both R.sup.1 and R.sup.2 are not amino; provided that if c is 0 and d is 1, then R.sup.1 is amino and R.sup.2 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; and provided that if c is 1 and d is 0, then R.sup.2 is amino and R.sup.1 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.