TDI-11861

Last updated
TDI-11861
TDI-11861 structure.png
Identifiers
  • [(3R)-4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]morpholin-3-yl]methanol
CAS Number
PubChem CID
Chemical and physical data
Formula C22H25ClF2N6O3
Molar mass 494.93 g·mol−1
3D model (JSmol)
  • C1COC[C@H](N1CCOC2=CC=CC=C2CC3=CN(N=C3C4=CC(=NC(=N4)N)Cl)C(F)F)CO
  • InChI=1S/C22H25ClF2N6O3/c23-19-10-17(27-22(26)28-19)20-15(11-31(29-20)21(24)25)9-14-3-1-2-4-18(14)34-8-6-30-5-7-33-13-16(30)12-32/h1-4,10-11,16,21,32H,5-9,12-13H2,(H2,26,27,28)/t16-/m1/s1
  • Key:XVGSKZXXLKUEIO-MRXNPFEDSA-N

TDI-11861 is a chemical compound which acts as a potent [1] and selective inhibitor of soluble adenylyl cyclase (sAC). [2] In animal studies it reversibly inhibits sperm motility, producing temporary infertility without hormonal side effects. While TDI-11861 is at an early developmental stage and is unlikely to be developed for medical uses in humans itself, it represents an important proof of concept which may potentially lead to the development of future male contraceptive drugs. [3] [4]

See also

Related Research Articles

<span class="mw-page-title-main">Adenylyl cyclase</span> Enzyme with key regulatory roles in most cells

Adenylate cyclase is an enzyme with systematic name ATP diphosphate-lyase . It catalyzes the following reaction:

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Cyclic guanosine monophosphate</span> Chemical compound

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface. Through protein kinases activation, cGMP can relax smooth muscle. cGMP concentration in urine can be measured for kidney function and diabetes detection.

<span class="mw-page-title-main">Guanylate cyclase</span> Lyase enzyme that synthesizes cGMP from GTP

Guanylate cyclase is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate:

Male contraceptives, also known as male birth control, are methods of preventing pregnancy by interrupting the function of sperm. The main forms of male contraception available today are condoms, vasectomy, and withdrawal, which together represented 20% of global contraceptive use in 2019. New forms of male contraception are in clinical and preclinical stages of research and development, but as of 2024, none have reached regulatory approval for widespread use.

<span class="mw-page-title-main">Heterotrimeric G protein</span> Class of enzymes

Heterotrimeric G protein, also sometimes referred to as the "large" G proteins are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called G protein-coupled receptors (GPCR), directly. These G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein.

<span class="mw-page-title-main">P2RY11</span> Protein-coding gene in the species Homo sapiens

P2Y purinoceptor 11 is a protein that in humans is encoded by the P2RY11 gene.

<span class="mw-page-title-main">ADCY6</span> Protein-coding gene in humans

Adenylyl cyclase type 6 is an enzyme that in humans is encoded by the ADCY6 gene.

<span class="mw-page-title-main">ADCY5</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.

<span class="mw-page-title-main">CAP1</span> Gene of the species Homo sapiens

Adenylyl cyclase-associated protein 1 is an enzyme that in humans is encoded by the CAP1 gene.

<span class="mw-page-title-main">ADCY7</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 7 is an enzyme that in humans is encoded by the ADCY7 gene.

<span class="mw-page-title-main">ADCY9</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 9 is an enzyme that in humans is encoded by the ADCY9 gene.

<span class="mw-page-title-main">ADCY4</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 4 is an enzyme that in humans is encoded by the ADCY4 gene.

<span class="mw-page-title-main">GUCY1A2</span> Protein-coding gene in the species Homo sapiens

Guanylate cyclase soluble subunit alpha-2 is an enzyme that in humans is encoded by the GUCY1A2 gene.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

<span class="mw-page-title-main">Bithionol</span> Chemical compound

Bithionol is an antibacterial, anthelmintic, and algaecide. It is used to treat Anoplocephala perfoliata (tapeworms) in horses and Fasciola hepatica.

<span class="mw-page-title-main">ADCY10</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase 10 also known as ADCY10 is an enzyme that, in humans, is encoded by the ADCY10 gene.

<span class="mw-page-title-main">JQ1</span> Chemical compound

JQ1 is a thienotriazolodiazepine and a potent inhibitor of the BET family of bromodomain proteins which include BRD2, BRD3, BRD4, and the testis-specific protein BRDT in mammals. BET inhibitors structurally similar to JQ1 are being tested in clinical trials for a variety of cancers including NUT midline carcinoma. It was developed by the James Bradner laboratory at Brigham and Women's Hospital and named after chemist Jun Qi. The chemical structure was inspired by patent of similar BET inhibitors by Mitsubishi Tanabe Pharma [WO/2009/084693]. Structurally it is related to benzodiazepines. While widely used in laboratory applications, JQ1 is not itself being used in human clinical trials because it has a short half life.

Soluble adenylyl cyclase (sAC) is a regulatory cytosolic enzyme present in almost every cell. sAC is a source of cyclic adenosine 3’,5’ monophosphate (cAMP) – a second messenger that mediates cell growth and differentiation in organisms from bacteria to higher eukaryotes. sAC differentiates from the transmembrane adenylyl cyclase (tmACs) – an important source of cAMP; in that sAC is regulated by bicarbonate anions and it is dispersed throughout the cell cytoplasm. sAC has been found to have various functions in physiological systems different from that of the tmACs.

<span class="mw-page-title-main">Photoactivated adenylyl cyclase</span>

Photoactivated adenylyl cyclase (PAC) is a protein consisting of an adenylyl cyclase enzyme domain directly linked to a BLUF type light sensor domain. When illuminated with blue light, the enzyme domain becomes active and converts ATP to cAMP, an important second messenger in many cells. In the unicellular flagellate Euglena gracilis, PACα and PACβ (euPACs) serve as a photoreceptor complex that senses light for photophobic responses and phototaxis. Small but potent PACs were identified in the genome of the bacteria Beggiatoa (bPAC) and Oscillatoria acuminata (OaPAC). While natural bPAC has some enzymatic activity in the absence of light, variants with no dark activity have been engineered (PACmn).

References

  1. Rossetti T, Ferreira J, Ghanem L, Buck H, Steegborn C, Myers RW, et al. (28 September 2022). "Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential". Frontiers in Physiology. 13: 1013845. doi: 10.3389/fphys.2022.1013845 . PMC   9554468 . PMID   36246105.
  2. Miller M, Rossetti T, Ferreira J, Ghanem L, Balbach M, Kaur N, et al. (November 2022). "Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates". Journal of Medicinal Chemistry. 65 (22): 15208–15226. doi:10.1021/acs.jmedchem.2c01133. PMC   9866367 . PMID   36346696. S2CID   253395810.
  3. Balbach M, Rossetti T, Ferreira J, Ghanem L, Ritagliati C, Myers RW, et al. (February 2023). "On-demand male contraception via acute inhibition of soluble adenylyl cyclase". Nature Communications. 14 (1): 637. Bibcode:2023NatCo..14..637B. doi:10.1038/s41467-023-36119-6. PMC   9929232 . PMID   36788210.
  4. WO 2022/232259,Balbach M, et al.,"Soluble Adenylyl Cyclase (sAC) Inhibitors and Uses Thereof",published 3 November 2022, assigned to Cornell Universityand Tri-Institutional Therapeutics Discovery Institute, Inc.